人全长Tau蛋白过度表达对线粒体分裂融合动态及细胞退变的影响
|
摘要
Tau蛋白既是组装微管和维持微管稳定性的重要骨架蛋白，也是AD脑内神经元纤维缠结的重要组分。最近研究发现AD患者或AD样动物大脑神经元有显著的线粒体形态分布异常和功能障碍。曾有研究报道被半胱天冬酶酶切后的tau在神经元可引起线粒体碎裂；AD病人神经元突触线粒体内富含N端截断tau蛋白且与突触病变和细胞器损伤相关。但是，AD脑内也存在全长tau蛋白，而tau蛋白是否影响线粒体动态，且其在细胞及神经退变中是否起作用未有研究报道。
目的：探讨人全长tau（htau）蛋白对细胞的线粒体分裂融合动态的影响及其在神经元退变中的作用。本研究在HEK293细胞、大鼠原代海马神经元、htau转基因动物水平进行了研究，旨在阐明过度表达tau蛋白对线粒体分裂、融合动态，线粒体功能，及其对细胞突起退变的影响及其机制。
方法：首先采用转染标记线粒体的质粒进行激光共聚焦成像技术结合线粒体形态分布定量分析，在HEK293细胞检测了稳定或瞬时htau过度表达对线粒体形状、分布的影响；采用ZEISS510激光共聚焦实时动态成像观测htau过度表达对细胞内线粒体分裂、融合动态，及细胞突起变化。使用免疫印迹、荧光定量PCR检测了细胞及动物过表达htau对线粒体分裂融合蛋白及mRNA水平的影响。给予放线菌酮抑制mRNA合成来证实tau蛋白是否通过影响Mfns的泛素化降解引起融合蛋白水平升高。进一步通过免疫印迹实验检测了tau过度表达对Mfns的泛素化修饰的影响。酶活性测定检测了tau过度表达时蛋白酶小体活性及Complex I活性的变化。测定了tau过度表达对细胞内ATP水平的影响。采用JC-1染色分析细胞内线粒体膜电位。分离线粒体检测了细胞及动物tau过度表达对线粒体PINK1水平的影响。采用碱或胰酶处理纯化的线粒体来检测tau蛋白是否分布在线粒体。
结果：在本实验中我们观察到以下结果：（1） htau稳定或瞬时过度表达引起大量HEK293细胞和大鼠原代海马神经元出现线粒体形态和分布障碍，表现为线粒体延长并聚集在细胞核周围，细胞突起部位分布的线粒体数目显著减少；(2)稳定或过度表达htau蛋白引起HEK293细胞线粒体融合速度显著加快；（3）htau过度表达引起HEK293细胞及小鼠海马线粒体融合蛋白水平Mfn1、Mfn2和OPA1水平显著升高;(4)下调融合蛋白Mfn1和Mfn2可部分逆转稳定表达htau的HEK293细胞的线粒体形态和分布障碍;(5)荧光定量PCR发现Mfn2mRNA水平升高；蛋白酶小体活性下降；抑制mRNA合成后， Mfn2水平高于对照组；（6）证明鼠tau蛋白可作为一个完整的膜蛋白定位于线粒体内膜，htau蛋白定位于线粒体膜间隙或靠近内膜处；（7）发现htau蛋白过度表达升高线粒体基础膜电位，PINK1水平显著下降；（8）发现在HEK293细胞htau过度表达早期不影响线粒体Complex I活性及ATP水平，晚期使二者下降，htau转基因动物内Complex I活性降低；（9）htau稳定过度表达或瞬时表达48h引起HEK293细胞出现退行性变化，突起变短变细，或出现肿胀、断裂等变化；（10）发现htau过度表达48h引起原代海马神经元的线粒体聚集在核周围或短树突内，突起内线粒体密度显著降低，突起数目显著减少，轴突长度显著缩短，突起出现串珠样断裂等退行性变化。
结论：htau过度表达早期引起线粒体融合加速、聚集在细胞核周围，晚期引起线粒体呼吸酶Comlex I活性降低和ATP生成减少，使细胞出现退行性改变。htau分布在线粒体升高线粒体基础膜电位，抑制PINK1转位于线粒体，使融合蛋白Mfns泛素化降解障碍，从而导致线粒体动态改变的机制。
Background: Intracellular accumulation of microtubule-associated protein tau is themajor cause of neurodegeneration in Alzheimer disease (AD) and other tauopathies;however, the mechanism underlying tau-induced neural dysfunction and degeneration iselusive. Since mitochondrial dynamics inblance was discovered in the autopsy neuron ofAlzheimer Disease patient. Therefore, the effect of tau overexpression on mitochondrialdynamics and cell degeneration was investigated in this study.
Objective: To study tau overexpression on mitochondrial fission/fusion dynamics andcell process degeneration, and the underlying mechanism.Methods: Immunofluorescence staining and live cell time-lapse imaging was used toquantification of mitochondrial size and distribution, Immunoblot was used to studyfission/fusion protein level, real time PCR was used to determine whether mRNA level offusion protein was increased by tau overexpression, Co-immunoprecipitation was used todetermine whether tau located in mitochondrial and whether tau overexpression changedthe ubiquitination of Mfns.20S proteasome activity assay to determine proteasome activity,and mitochondrial membrane potential assay with JC-1staining, Complex I activity assayand ATP level assay was to determine mitochondrial function. Extract mitochondrial fromHEK293cells and tau-/-or htau transgenic mice to detect the level of PINK1. Alkaline andTrypsin treatment of isolated mitochondria was used to determine tau location.
Results: In the present study, we found that expression of human full length tau (htau)promoted mitochondria fusion and their perinuclear accumulation in HEK293cells and primary hippocampal neurons. At the molecular level, expression of htau increased thelevels of mitofusins Mfn1, Mfn2and OPA1with no effects on fission protein Fis1, andsimultaneous downregulation of Mfn1or Mfn2but not OPA1attenuates the htau-inducedmitochondrial fusion. We also found that htau was located into the mitochondria, and themitochondrial allocation of htau increased the membrane potential with reduced levels ofPINK1and ubiquitinated Mfn1/Mfn2. Finally, retraction and deprivation of the neuronalprocesses with decreased ATP level and complex I activity were observed followed byperinuclear mitochondrial accumulation at tau overexpression48h.
Conclusion: These data together indicated that htau overexpression enhancesmitochondria fusion via cumulating mitofusins without changing mitochondrial function atearly stage, while at later stage causes neurodegeneration via impairing mitochondrialfunctions. It suggests that blocking htau accumulation may protect againstneurodegeneration through rescuing mitochondrial functions.
目的：探讨人全长tau（htau）蛋白对细胞的线粒体分裂融合动态的影响及其在神经元退变中的作用。本研究在HEK293细胞、大鼠原代海马神经元、htau转基因动物水平进行了研究，旨在阐明过度表达tau蛋白对线粒体分裂、融合动态，线粒体功能，及其对细胞突起退变的影响及其机制。
方法：首先采用转染标记线粒体的质粒进行激光共聚焦成像技术结合线粒体形态分布定量分析，在HEK293细胞检测了稳定或瞬时htau过度表达对线粒体形状、分布的影响；采用ZEISS510激光共聚焦实时动态成像观测htau过度表达对细胞内线粒体分裂、融合动态，及细胞突起变化。使用免疫印迹、荧光定量PCR检测了细胞及动物过表达htau对线粒体分裂融合蛋白及mRNA水平的影响。给予放线菌酮抑制mRNA合成来证实tau蛋白是否通过影响Mfns的泛素化降解引起融合蛋白水平升高。进一步通过免疫印迹实验检测了tau过度表达对Mfns的泛素化修饰的影响。酶活性测定检测了tau过度表达时蛋白酶小体活性及Complex I活性的变化。测定了tau过度表达对细胞内ATP水平的影响。采用JC-1染色分析细胞内线粒体膜电位。分离线粒体检测了细胞及动物tau过度表达对线粒体PINK1水平的影响。采用碱或胰酶处理纯化的线粒体来检测tau蛋白是否分布在线粒体。
结果：在本实验中我们观察到以下结果：（1） htau稳定或瞬时过度表达引起大量HEK293细胞和大鼠原代海马神经元出现线粒体形态和分布障碍，表现为线粒体延长并聚集在细胞核周围，细胞突起部位分布的线粒体数目显著减少；(2)稳定或过度表达htau蛋白引起HEK293细胞线粒体融合速度显著加快；（3）htau过度表达引起HEK293细胞及小鼠海马线粒体融合蛋白水平Mfn1、Mfn2和OPA1水平显著升高;(4)下调融合蛋白Mfn1和Mfn2可部分逆转稳定表达htau的HEK293细胞的线粒体形态和分布障碍;(5)荧光定量PCR发现Mfn2mRNA水平升高；蛋白酶小体活性下降；抑制mRNA合成后， Mfn2水平高于对照组；（6）证明鼠tau蛋白可作为一个完整的膜蛋白定位于线粒体内膜，htau蛋白定位于线粒体膜间隙或靠近内膜处；（7）发现htau蛋白过度表达升高线粒体基础膜电位，PINK1水平显著下降；（8）发现在HEK293细胞htau过度表达早期不影响线粒体Complex I活性及ATP水平，晚期使二者下降，htau转基因动物内Complex I活性降低；（9）htau稳定过度表达或瞬时表达48h引起HEK293细胞出现退行性变化，突起变短变细，或出现肿胀、断裂等变化；（10）发现htau过度表达48h引起原代海马神经元的线粒体聚集在核周围或短树突内，突起内线粒体密度显著降低，突起数目显著减少，轴突长度显著缩短，突起出现串珠样断裂等退行性变化。
结论：htau过度表达早期引起线粒体融合加速、聚集在细胞核周围，晚期引起线粒体呼吸酶Comlex I活性降低和ATP生成减少，使细胞出现退行性改变。htau分布在线粒体升高线粒体基础膜电位，抑制PINK1转位于线粒体，使融合蛋白Mfns泛素化降解障碍，从而导致线粒体动态改变的机制。
Background: Intracellular accumulation of microtubule-associated protein tau is themajor cause of neurodegeneration in Alzheimer disease (AD) and other tauopathies;however, the mechanism underlying tau-induced neural dysfunction and degeneration iselusive. Since mitochondrial dynamics inblance was discovered in the autopsy neuron ofAlzheimer Disease patient. Therefore, the effect of tau overexpression on mitochondrialdynamics and cell degeneration was investigated in this study.
Objective: To study tau overexpression on mitochondrial fission/fusion dynamics andcell process degeneration, and the underlying mechanism.Methods: Immunofluorescence staining and live cell time-lapse imaging was used toquantification of mitochondrial size and distribution, Immunoblot was used to studyfission/fusion protein level, real time PCR was used to determine whether mRNA level offusion protein was increased by tau overexpression, Co-immunoprecipitation was used todetermine whether tau located in mitochondrial and whether tau overexpression changedthe ubiquitination of Mfns.20S proteasome activity assay to determine proteasome activity,and mitochondrial membrane potential assay with JC-1staining, Complex I activity assayand ATP level assay was to determine mitochondrial function. Extract mitochondrial fromHEK293cells and tau-/-or htau transgenic mice to detect the level of PINK1. Alkaline andTrypsin treatment of isolated mitochondria was used to determine tau location.
Results: In the present study, we found that expression of human full length tau (htau)promoted mitochondria fusion and their perinuclear accumulation in HEK293cells and primary hippocampal neurons. At the molecular level, expression of htau increased thelevels of mitofusins Mfn1, Mfn2and OPA1with no effects on fission protein Fis1, andsimultaneous downregulation of Mfn1or Mfn2but not OPA1attenuates the htau-inducedmitochondrial fusion. We also found that htau was located into the mitochondria, and themitochondrial allocation of htau increased the membrane potential with reduced levels ofPINK1and ubiquitinated Mfn1/Mfn2. Finally, retraction and deprivation of the neuronalprocesses with decreased ATP level and complex I activity were observed followed byperinuclear mitochondrial accumulation at tau overexpression48h.
Conclusion: These data together indicated that htau overexpression enhancesmitochondria fusion via cumulating mitofusins without changing mitochondrial function atearly stage, while at later stage causes neurodegeneration via impairing mitochondrialfunctions. It suggests that blocking htau accumulation may protect againstneurodegeneration through rescuing mitochondrial functions.
引文
1. Alloul K, et al.（1998）Alzheimer's disease: a review of the disease, its epidemiologyand economic impact. Arch Gerontol Geriatr.27(3): p.189-221.
2. Grundke-Iqbal I, et al.(1986) Microtubule-associated protein tau: A component ofAlzheimer paired helical filaments. J Biol Chem.261:6084–6089.
3. Iqbal K, et al.(1989) Identification and localization of a tau peptide to paired helicalfilaments of Alzheimer disease. Proc Natl Acad Sci USA.86:5646-5650.
4. Berger Z, et al.(2007) Accumulation of pathological tau species and memory loss in aconditional model of tauopathy. J Neurosci.27(14): p.3650-3662.
5. Andorfer C, et al.（2003）Hyperphosphorylation and aggregation of tau in miceexpressing normal human tau isoforms. J Neurochem.86(3): p.582-590.
6. Boutajangout A, D Quartermain and EM Sigurdsson (2010) Immunotherapy targetingpathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci.30(49): p.16559-16566.
7. Van der Jeugd A, et al.（2011） Hippocampal tauopathy in tau transgenic micecoincides with impaired hippocampus-dependent learning and memory, and attenuatedlate-phase long-term depression of synaptic transmission. Neurobiol Learn Mem.95(3): p.296-304.
8. Benard, G. and M. Karbowski.(2009) Mitochondrial fusion and division: Regulationand role in cell viability. Semin Cell Dev Biol.20(3): p.365-374.
9. Chen H and DC Chan (2009) Mitochondrial dynamics--fusion, fission, movement, andmitophagy--in neurodegenerative diseases. Hum Mol Genet.18(R2): p. R169-176.
10. Smirnova E, et al.(2001) Dynamin-related protein Drp1is required for mitochondrialdivision in mammalian cells. Mol Biol Cell,12(8): p.2245-2256.
11. James DI, et al.(2003) hFis1, a novel component of the mammalian mitochondrialfission machinery. J Biol Chem.278(38): p.36373-36379.
12. Wells RC, et al.(2007) Direct binding of the dynamin-like GTPase, Dnm1, tomitochondrial dynamics protein Fis1is negatively regulated by the Fis1N-terminalarm. J Biol Chem.282(46): p.33769-33775.
13. Suzuki M, et al.(2003) The solution structure of human mitochondria fission proteinFis1reveals a novel TPR-like helix bundle. J Mol Biol.334(3): p.445-458.
14. Santel A. and MT Fuller.（2001） Control of mitochondrial morphology by a humanmitofusin. J Cell Sci.114(Pt5): p.867-874.
15. Rojo M, et al.（2002）Membrane topology and mitochondrial targeting of mitofusins,ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci.115(Pt8): p.1663-1674
16Chen H, A Chomyn and DC Chan.(2005) Disruption of fusion results inmitochondrial heterogeneity and dysfunction. J Biol Chem.280(28): p.26185-26192.
17. Frezza C, et al.(2006) OPA1controls apoptotic cristae remodeling independentlyfrom mitochondrial fusion. Cell.126(1): p.177-189.
18. Cipolat S, et al.(2004) OPA1requires mitofusin1to promote mitochondrial fusion.Proc Natl Acad Sci U S A.101(45): p.15927-15932.
19. Chen H, et al.(2010) Mitochondrial fusion is required for mtDNA stability in skeletalmuscle and tolerance of mtDNA mutations. Cell.141(2): p.280-289.
20. Pellegrini L. and L Scorrano.(2007) A cut short to death: Parl and Opa1in theregulation of mitochondrial morphology and apoptosis. Cell Death Differ.14(7): p.1275-1284.
21. Jahani-Asl A, et al.(2011) The mitochondrial inner membrane GTPase, optic atrophy1(Opa1), restores mitochondrial morphology and promotes neuronal survivalfollowing excitotoxicity. J Biol Chem.286(6): p.4772-4782.
22. Twig G, et al.(2008) Fission and selective fusion govern mitochondrial segregation andelimination by autophagy. EMBO J.27(2): p.433-446.
23. Karbowski M, et al.(2002) Spatial and temporal association of Bax withmitochondrial fission sites, Drp1, and Mfn2during apoptosis. J Cell Biol.159(6): p.931-938.
24. Wang X, et al.(2008) Amyloid-beta overproduction causes abnormal mitochondrialdynamics via differential modulation of mitochondrial fission/fusion proteins. ProcNatl Acad Sci U S A.105(49): p.19318-19323.
25. Wang X, et al.(2009) Impaired balance of mitochondrial fission and fusion inAlzheimer's disease. J Neurosci.29(28): p.9090-9103.
26. Rhein V, et al.(2009) Amyloid-beta and tau synergistically impair the oxidativephosphorylation system in triple transgenic Alzheimer's disease mice. Proc NatlAcad Sci U S A.106(47): p.20057-20062.
27. David DC, et al.(2005) Proteomic and functional analyses reveal a mitochondrialdysfunction in P301L tau transgenic mice. J Biol Chem.280(25): p.23802-23814.
28. Kopeikina KJ, et al.(2011) Tau accumulation causes mitochondrial distributiondeficits in neurons in a mouse model of tauopathy and in human Alzheimer's diseasebrain. Am J Pathol.179(4): p.2071-2082.
29. Quintanilla RA, et al.(2009) Caspase-cleaved tau expression induces mitochondrialdysfunction in immortalized cortical neurons: implications for the pathogenesis ofAlzheimer disease. J Biol Chem.284(28): p.18754-18766.
30. Amadoro G, et al.（2010） A NH2tau fragment targets neuronal mitochondria at ADsynapses: possible implications for neurodegeneration. J Alzheimers Dis.21(2): p.445-470.
31. Li HL, et al.(2007) Phosphorylation of tau antagonizes apoptosis by stabilizingbeta-catenin, a mechanism involved in Alzheimer's neurodegeneration. Proc NatlAcad Sci U S A.104(9): p.3591-6.
32. Wang ZF, et al.(2010) Overexpression of tau proteins antagonizesamyloid-beta-potentiated apoptosis through mitochondria-caspase-3pathway in N2acells. J Alzheimers Dis.20(1): p.145-57.
33. Erturk A, et al.(2007) Disorganized microtubules underlie the formation of retractionbulbs and the failure of axonal regeneration. J Neurosci.27(34): p.9169-80.
34. Gandhi S, et al.(2006) PINK1protein in normal human brain and Parkinson's disease.Brain.129(Pt7): p.1720-31.
35. Song Z, et al.(2009) Mitofusins and OPA1mediate sequential steps in mitochondrialmembrane fusion. Mol Biol Cell.20(15): p.3525-32.
36. Cohen MM, et al.(2008) Ubiquitin-proteasome-dependent degradation of a mitofusin,a critical regulator of mitochondrial fusion. Mol Biol Cell.19(6): p.2457-64.
37Matsuda N, et al.(2010) PINK1stabilized by mitochondrial depolarization recruitsParkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol.189(2): p.211-21.
38Nickie C Chan, et al.(2011) Broad activation of ubiquitin proteasome system byparkin is critical for mitophagy. Hum Mol Genet.20(9): p.1726-1737.
39. Atsushi Tanaka, et al.(2011) Proteasome and P97mediate mitophagy and degradationof mitofusins induced by parkin. J Cell Biol.191: p.1367-1380.
40Sorokin AV, Kim ER, Ovchinnikov LP.(2009) Proteasome system of proteindegradation and processing. Biochemistry (Mosc).74: p.1411-1442.
41. Arriagada PV, et al.（1992） Neurofibrillary tangles but not senile plaques parallelduration and severity of Alzheimer's disease. Neurology.42(3Pt1): p.631-639.
42. Hirai K, et al.(2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci.21(9): p.3017-3023.
43. de Calignon A, et al.(2010) Caspase activation precedes and leads to tangles. Nature.464:1201-1204.
44. Tondera D, et al.(2009) SLP-2is required for stress-induced mitochondrialhyperfusion. EMBO J.28(11): p.1589-600.
45LaPointe NE, et al.(2009) The amino terminus of tau inhibits kinesin-dependentaxonal transport: implications for filament toxicity. J Neurosci Res.87(2): p.440-451.
46Dixit R, Ross JL, Goldman YE, Holzbaur EL.(2008) Differential regulation of dyneinand kinesin motor proteins by tau. Science.319(5866):p.1086-1089.
47Misko A, et al.(2010) Mitofusin2is necessary for transport of axonal mitochondriaand interacts with the Miro/Milton complex. J Neurosci.30(12): p.4232-4240.
48. Glauser L, et al.（2011）Parkin promotes the ubiquitination and degradation of themitochondrial fusion factor mitofusin1. J Neurochem.118(4): p.636-645.
49Haque ME, et al.(2008) Cytoplasmic Pink1activity protects neurons fromdopaminergic neurotoxin MPTP. Proc Natl Acad Sci U S A.105(5): p.1716-1721.
50Zhou C, et al.(2008) The kinase domain of mitochondrial PINK1faces the cytoplasm.Proc Natl Acad Sci U S A.105(33): p.12022-7.
51Wilhelmus MM, et al.(2011) Association of Parkinson disease-related protein PINK1with Alzheimer disease and multiple sclerosis brain lesions. Free Radic Biol Med.50(3): p.469-76.
52Canu N, Filesi I, Pristerà A, Ciotti MT, Biocca S (2011) Altered IntracellularDistribution of PrPC and Impairment of Proteasome Activity in Tau OverexpressingCortical Neurons. J Alzheimers Dis27: p.603-613.
53Mandelkow EM, et al.（1996） Structure, microtubule interactions, andphosphorylation of tau protein. Ann N Y Acad Sci. Jan17;777:96-106.
54Andorfer C, et al.(2003) Hyperphosphorylation and aggregation of tau in miceexpressing normal human tau isoforms. J Neurochem.86(3):p.582-590.
55Andorfer C, et al.(2005) Cell-cycle reentry and cell death in transgenic miceexpressing nonmutant human tau isoforms. J Neurosci.25(22): p.5446-5454.
56Ando K,et al.(2011) Accelerated human mutant tau aggregation by knocking outmurine tau in a transgenic mouse model. Am J Pathol.178(2): p.803-816.
57Shahpasand K, et al.(2012) Regulation of mitochondrial transport andinter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated inAlzheimer's disease. J Neurosci.32(7):p.2430-2441.
58Poorki P, et al.(2001) A genomic sequence analysis of the mouse and humanmicrotubule-associated protein tau. Mamm Genome.12:700-712.
59Cristian ALR, Diana LCC, Urmi S, et al.(2011) Tau oligomers impair memory andinduce synaptic and mitochondrial dysfunction in wild-type mice. MolNeurodegeneration. Jun6;6:39.
60. Li Q, et al.(2010) ALS-linked mutant superoxide dismutase1(SOD1) altersmitochondrial protein composition and decreases protein import. Proc Natl Acad Sci US A107:21146-21151
61Kimura T, et al.（2010）Aggregation of detergent-insoluble tau is involved in neuronalloss but not in synaptic loss. J Biol Chem.285(49): p.38692-386999.
1I. Grundke-Iqbal, K. Iqbal, M. Quinlan, Y.C. Tung, M.S. Zaidi, H.M. Wisniewski,Microtubule-associated protein tau: a component of Alzheimer paired helical filament,J. Biol. Chem.261(1986)6084-6089.
2V.M. Lee, B.J. Balin, L.J. Otvos, J.Q. Trojanowski, A68: a major subunit of the pairedhelical filaments and derivatized forms of normal tau, Science251(1991)675-678.
3C.X. Gong, T. Lidsky, J. Wegiel, L. Zuck, I. Grundke-Iqbal, K. Iqbal, Phosphorylationof microtubule-associated protein tau is regulated by protein phosphatase2A inmammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease,J. Biol. Chem.275(2000)5535-5544.
4F. Liu, I. Grundke-Iqbal, K. Iqbal, C.X. Gong, Contributions of protein phosphatasesPP1, PP2A, PP2B and PP5to the regulation of tau phosphorylation, Eur. J. Neurosci.22(2005)1942-1950.
5E. Planel, K. Yasutake, S.C. Fujita, K. Ishiguro, Inhibition of phosphatase2Aoverridestau protein kinase1/glycogen synthase kinase3and cyclin-dependent kinase5inhibition and results in tau hyperphosphorylation in the hippocampus of starvedmouse, J. Biol. Chem.276(2000)34298-34306.
6A. Takashima, GSK-3is essential in the pathogenesis of Alzheimer’s disease, J.Alzheimers Dis.9(2006)309-317.
7J.Avila, J.Dí az-Nido, Tangling with hypothermia, Nat. Med.10(2004)460-461.
8J.Z. Wang, C.X. Gong, T. Zaidi, I. Grundke-Iqbal, K. Iqbal, Dephosphorylation ofAlzheimer paired helical filaments by protein phosphatase-2A and-2B, J. Biol. Chem.270(1995)4854-4860.
9A. Takashima, K. Noguchi, G. Michel, M. Mercken, M. Hoshi, K. Ishiguro, K.Imahori, Exposure of rat hippocampal neurons to amyloid beta peptide (25–35)induces the inactivation of phosphatidyl inositol-3kinase and the activation of tauprotein kinase I/glycogen synthase kinase-3beta, Neurosci. Lett.203(1996)33-36.
10K. Ishiquro, A. Shiratsuchi, S. Sato, A. Omori, M. Arioka, S. Kobayashi, T. Uchida, K.Imahori, Glycogen synthase kinase3beta is identical to tau protein kinase I generatingseveral epitopes of paired helical flaments, FEBS Lett.325(1993)167-172.
11D.P. Hanger, B.H. Anderton, W. Noble, Tau phosphorylation: the therapeutic challengefor neurodegenerative disease, Trends Mol. Med.15(2009)112-119.
12] J. Z. Wang, F. Liu, Microtubule-associated protein tau in development,degeneration and protection of neurons, Prog. Neurobiol.85(2008)148-175.
13S. Lovestone, C.H. Reynolds, D. Latimer, D.R. Davis, B.H. Anderton, J.M. Gallo, D.Hanger, S. Mulot, B. Marquardt, S. Stabel, et al., Alzheimer’s disease-likephosphorylation of the microtubule-associated protein tau by glycogen synthasekinase-3in transfected mammalian cells, Curr. Biol.4(1994)1077-1086.
14J.R. Munoz-Montano, F.J. Moreno, J. Avila, J. Diaz-Nido, Lithium inhibitsAlzheimer’s disease-like tau protein phosphorylation in neurons, FEBS Lett.411(1997)183-188.
15M. Hong, D.C. Chen, P.S. Klein, V.M. Lee, Lithium reduces tau phosphorylation byinhibition of glycogen synthase kinase-3, J. Biol. Chem.272(1997)25326-25332.
16S.J. Liu, A.H. Zhang, H.L. Li, O. Wang, H.M. Deng, W.J. Netzer, H.X. Xu, J.Z. Wang,Overactivation of glycogen synthase kinase-3by inhibition of phosphoinositol-3kinase and protein kinase C leads to hyperphosphorylation of tau and impairment ofspatial memory, J. Neurochem.87(2003)1333-1344.
17I. Ferrer, M. Barrachina, B. Puig, Glycogen synthase kinase-3is associated withneuronal and glial hyperphosphorylated tau deposits in Alzheimer’s disease, Pick’sdisease, progressive supranuclear palsy and corticobasal degeneration, Acta.Neuropathol.(Berl)104(2002)583-591.
18J.J. Pei, E. Braak, H. Braak, I. Grundke-Iqbal, K. Iqbal, B. Winblad, R.F. Cowburn,Distribution of active glycogen synthase kinase3(GSK-3) in brains staged forAlzheimer disease neurofbrillary changes, J. Neuropathol. Exp. Neurol.58(1999)1010-1019.
19J.J. Lucas, F. Hernández, P. Gómez-Ramos, M.A. Morán, R. Hen, J. Avila,Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration inGSK-3beta conditional transgenic mice, EMBO J.20(2001)27-39.
20C.X. Gong, T.J. Singh, I. Grundke-Iqbal, K. Iqbal, Phosphoprotein phosphataseactivities inAlzheimer disease brain, J. Neurochem.61(1993)921-927.
21J.Z. Wang, I. Grundke-Iqbal, K. Iqbal, Tau is phosphorylated by GSK-3at several sitesfound in AD and its biological activity markedly inhibited only after it isprephosphorylated byA-kinase, FEBS Lett.436(1998)28-34.
22J.Z. Wang, I. Grundke-Iqbal, K. Iqbal, Kinases and phosphatases and tau sites nvolvedinAlzheimer neurofibrillary degeneration, Eur. J. Neurosci.25(2007)59-68.
23L. Sun, S.Y. Liu, X.W. Zhou, X.C. Wang, R. Liu, Q. Wang, J.Z. Wang, Inhibition ofprotein phosphatase2a-and protein phosphatase1-induced tau hyperphosphorylationand impairment of spatial memory retention in rats, Neuroscience118(2003)1175-1182.
24Q. Tian, Z.Q. Lin, X.C. Wang, J. Chen, Q. Wang, C.X. Gong, J.Z. Wang, Injection ofokadaic acid into the meynert nucleus basalis of rat brain induces decreasedacetylcholine level and spatial memory deficit, Neuroscience126(2004)277-184.
25M. Li, H. Guo, Z. Damuni, Purification and characterization of two potent heat-stableprotein inhibitors of protein phosphatase2A from bovine kidney, Biochemistry34(1995)1988-1996.
26I. Tsujio, T. Zaidi, J. Xu, L. Kotula, I. Grundke-Iqbal,K. Iqbal, Inhibitors of proteinphosphatase-2A from human brain structures, immunocytological localization andactivities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau,FEBS Lett.579(2005)363-372.
27H. Tanimukai, I. Grundke-Iqbal, K. Iqbal, Upregulation of inhibitors of proteinphosphatase-2A in Alzheimer’s disease, Am. J. Pathol.166(2005)1761-1771.
28G.P. Liu, Y. Zhang, X.Q. Yao, C.E. Zhang, J. Fang, Q. Wang, J.Z. Wang, Activation ofglycogen synthase kinase-3inhibits protein phosphatase-2A and the underlyingmechanisms, Neurobiol.Aging29(2008)1348-1358.
29J.P. ten Klooster, I. Leeuwen, N. Scheres, E.C. Anthony, P.L. Hordijk, Rac1-inducedcell migration requires membrane recruitment of the nuclear oncogene SET, EMBO J.26(2007)336-345.
30T.R. Brummelkamp, R. Bernards, R. Agami, A system for stable expression of shortinterfering RNAs in mammalian cells, Science296(2002)550-553.
31S.M. Elbashir, J. Harborth, W. Lendeckel, A. Yalcin, K. Weber, T. Tuschl, Duplexesof21-nucleotide RNAs mediate RNA interference in cultured mammalian cells,Nature411(2001)494-498.
32L. Naldini, U. Bl mer, P. Gallay, D. Ory, R. Mulligan, F.H. Gage, I.M. Verma, D.Trono, In vivo gene delivery and stable transduction of nondividing cells by alentiviral vector, Science272(1996)263-267.
33R.A. Marr, E. Rockenstein, A. Mukherjee, M.S. Kindy, L.B. Hersh, F.H. Gage, I.M.Verma, E. Masliah, Neprilysin gene transfer reduces human amyloid pathology intransgenic mice, J. Neurosci.23(2003)1992-1996.
34M. Polydoro, C.M. Acker, K. Duff, P.E. Castillo, P. Davies, Age-dependentimpairment of cognitive and synaptic function in the htau mouse model of taupathology, J Neurosci.29(2009)10741-10749.
35B.K. Kaspar, B. Vissel, T. Bengoechea, S. Crone, L. Randolph-Moore, R. Muller, E.P.Brandon, D. Schaffer, I.M. Verma, K.F. Lee, S.F. Heinemann, F.H. Gage,Adeno-associated virus effectively mediates conditional gene modification in the brain,Proc. Natl.Acad. Sci. USA99(2002)2320-2325.
36M.R. Zarrindast, M. Bananej, A. Khalilzadeh, S. Fazli-Tabaei, A. Haeri-Rohani, A.Rezayof, Influence of intracerebroventricular administration of dopaminergic drugs onmorphine state-dependent memory in the step-down passive avoidance test. Neurobiol.Learn Mem.86(2006)286-292.
37C.S. Woolley, B.S. McEwen, Estradiol mediates fluctuation in hippocampal synapsedensity during the estrous cycle in the adult rat. J Neurosci12(1992)2549-2554.
38M. Li, A. Makkinje, Z. Damuni, The myeloid leukemia-associated protein SET is apotent inhibitor of protein phosphatase2A, J. Biol. Chem.271(1996)11059-11062.
39G.P. Liu, W. Wei, X. Zhou, Y. Zhang, H.H. Shi, J. Yin, X.Q. Yao, C.X. Peng, J. Hu, Q.Wang, H.L. Li, J.Z. Wang, I(2)(PP2A) regulates p53and Akt correlatively and leadsthe neurons to abort apoptosis, Neurobiol. Aging33(2012)254-264.
40D.A. Cross, D.R. Alessi, P. Cohen, M. Andjelkovich, B.A. Hemmings, Inhibition ofglycogen synthase kinase-3by insulin mediated by protein kinase B, Nature378(1995)785-789.
41M. Shaw, P. Cohen, D.R. Alessi, Further evidence that the inhibition of glycogensynthase kinase-3beta by IGF-1is mediated by PDK1/PKB-induced phosphorylationof Ser-9and not by dephosphorylation of Tyr-216, FEBS Lett.416(1997)307-311.
42X. Fang, S.X. Yu, Y. Lu, Jr. Bast RC, J.R. Woodgett, G.B. Mills, Phosphorylationand inactivation of glycogen synthase kinase3by protein kinase A, Proc. Natl. Acad.Sci. USA97(2000)11960-11965.
43X. Wang, J. Blanchard, E. Kohlbrenner, N. Clement, R.M. Linden, A. Radu, I.Grundke-Iqbal, K. Iqbal, The carboxy-terminal fragment of inhibitor-2of proteinphosphatase-2A induces Alzheimer disease pathology and cognitive impairment,FASEB J.24(2010)4420-4432.
44S. Peineau, C. Taqhibiglou, T.P. Wonq, L. Liu, J. Lu, E. Lo, D. Wu, E. Saule, T.Bouschet, P. Matthews, J.T. Isaac, Z.A. Bortolotto, Y.T. Wang, G.L. Collinqridge, LTPinhibits LTD in the hippocampus via regulation of GSK-3beta, Neuron53(2007)703-717.
45T. Kimura, S. Yamashhita, S. Nakao, J.M. Park, M. Murayama, T. Mizoroki, Y.Yoshiike, N. Sahara, A. Takashima, GSK-3beta is required for memory reconsolidationin adult brain, PLos One3(2008) e3540.
46T. Engel, F. Hernández, J. Avila, J.J. Lucas, Full reversal of Alzheimer’s disease-likephenotype in a mouse model with conditional overexpression of glycogen synthasekinase-3, J. Neurosci.26(2006)5083-5090.
47E.S. Emamian, D. Hall, M.J. Birnbaum, M. Krayiorou, J.A. Goqos, Convergentevidence for impaired AKT1-GSK-3beta signaling in schizophrenia, Nat. Genet.6(2004)131-137.
48K. Leroy, Z. Yilmaz, J.P. Brion, Increase level of active GSK-3β in Alzheimer’sdisease and accumulation in argyrophilic grains and in neurons at different stages ofneurofibrillary degeneration, Neuropathol. Appl. Neurobiol.33(2007)43-55.
49A. Hye, F. Kerr, N. Archer, C. Foy, M. Poppe, R. Brown, G. Hamilton, J. Powell, B.Anderton, S. Lovestone, Glycogen synthase kinase-3is increased in white cells earlyAlzheimer’s disease, Neurosci. Lett.373(2005)1-4.
50A.E. Aplin, G.M. Gibb, J.S. Jacobsen, J.M. Gallo, B.H. Anderton, In vitrophosphorylation of the cytoplasmic domain of the amyloid precursor protein byglycogen synthase kinase-3, J. Neurochem.67(1996)699-707.
51A. Takashima, K. Noguchi, K. Sato, T. Hoshino, K. Imahori, Tau protein kinase I isessential for amyloid-protein-induced neurotoxicity, Proc. Natl. Acad. Sci. USA90(1993)7789-7793.
52A. Takashima, M. Murayama, O. Murayama, T. Kohno, T. Honda, K. Yasutake, N.Nihonmatsu, M. Mercken, H. Yamaguchi, S. Sugihara, B. Wolozin, Presenilin1associates with glycogen synthase kinase-3and its substrate tau, Proc. Natl. Acad. Sci.USA95(1998)9637-9641.
53R. Gantier, D. Gilbert, C. Dumanchin, D. Campion, D. Davoust, F. Toma, T. Frebourg,The pathogenic L392V mutation of presenilin1decreases the affinity to glycogensynthase kinase-3, Neurosci. Lett.283(2000)217-220.
54C.A. Grimes, R.S. Jope, The multifaceted roles of glycogen synthase kinase3incellular signaling, Prog. Neurobiol.65(2001)391-426.
55R. Gómez-Sintes, F. Hernández, J.J. Lucas, J. Avila, Gsk-3mouse models to studyneuronal apoptosis and neurodegeneration, Front Mol. Neurosci.4(2011)45.
56J. Avila, F. Lim, F. Moreno, C. Belmonte,A.C. Cuello, Tau function and dysfunction inneurons: its role in neurodegenerative disorders, Mol. Neurobiol.25(2002)213-231.
57D. Terwel, R. Lasrado, J. Snauwaert, E. Vandeweert, C. Van Haesendonck, P.Borghgraef, F. Van Leuven, Changed conformation of mutant Tau-P301L underlies themoribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2Ntransgenic mice, J. Biol. Chem.280(2005):3963-3973.
1. Zhang P, Hinshaw JE.(2001) Three-dimensional reconstruction of dynamin in theconstricted state.Nat Cell Biol.3(10): p.922-926.
2. Smirnova E, et al.(2001) Dynaminrelated protein Drp1is required for mitochondrialdivision in mammalian cells. Mol Biol Cell.12:p.2245-2256.
3. Smirnova E, et al.(1998) A human dynamin-related protein controls the distribution ofmitochondria. J Cell Biol.143:p.351-358.
4. KR Pitts, et al.(1999) The Dynamin-like Protein DLP1Is Essential for NormalDistribution and Morphology of the Endoplasmic Reticulum and Mitochondria inMammalian Cells. Mol Biol Cell.10(12):p.4403–4417.
5. Glenn Marsboom, et al.(2012) Dynamin-Related Protein1–Mediated MitochondrialMitotic Fission Permits Hyperproliferation of Vascular Smooth Muscle Cells andOffers a Novel Therapeutic Target in Pulmonary Hypertension. Circulation Research.Circresaha.111:263848.
6. Taguchi N, et al.(2007) Mitotic phosphorylation of dynamin-related GTPaseDrp1participates in mitochondrial fission. J Biol Chem.282: p.11521–11529.
7. Cribbs JT, Strack S.(2007) Reversible phosphorylation of Drp1by cyclicAMP-dependent protein kinase and calcineurin regulates mitochondrial fission and celldeath. EMBO Rep.8: p.939–944.
8. Chang CR, Blackstone C.(2007) Cyclic AMP-dependent protein kinasephosphorylation of Drp1regulates its GTPase activity and mitochondrial morphology.J Biol Chem.282: p.21583–21587.
9. Xin Qi, et al.(2011) Aberrant mitochondrial fission in neurons induced by proteinkinase Cδ under oxidative stress conditions in vivo. Mol Biol Cell.22(2):256–265.
10. Kashatus DF, et al.(2011) RALA and RALBP1regulate mitochondrial fission atmitosis. Nat Cell Biol.13(9):p.1108-1115.
11. Liu JP, et al.(1996) Calcium binds dynamin I and inhibits its GTPase activity. JNeurochem.66(5): p.2074-2081.
12. Breckenridge DG, et al.(2003) Caspase cleavage product of BAP31inducesmitochondrial fission through endoplasmic reticulum calcium signals, enhancingcytochrome c release to the cytosol. J Cell Biol.160: p.1115-1127
13. Hom JR, et al.(2007) Thapsigargin induces biphasic fragmentation of mitochondriathrough calcium-mediated mitochondrial fission and apoptosis. J Cell Physiol.212(2):p.498-508.
14. Cereghetti GM, et al.(2008) Dephosphorylation by calcineurin regulates translocationof Drp1to mitochondria. Proc Natl Acad Sci U S A.105: p.15803–15808.
15. Han XJ, et al.(2008) CaM kinase I alpha-induced phosphorylation of Drp1regulatesmitochondrial morphology. J Cell Biol.182: p.573–585.
16. Wang W, et al.(2012) Mitochondrial fission triggered by hyperglycemia is mediated byROCK1activation in podocytes and endothelial cells. Cell Metabolism.15: p.186-200.
17.17． Cho DH, et al.(2009) S-nitrosylation of Drp1mediates beta-amyloid-relatedmitochondrial fission and neuronal injury. Science.324: p.102–105.
18. Harder Z, Zunino R, McBride H.(2004) Sumo1conjugates mitochondrial substratesand participates in mitochondrial fission. Curr Biol.14: p.340–345.
19. Claudia Figueroa-Romero, et al.(2009) SUMOylation of the mitochondrial fissionprotein Drp1occurs at multiple nonconsensus sites within the B domain and is linkedto its activity cycle. The FASEB Journal. p.11:3917-3927.
20. Liu QA, Shio H.(2008) Mitochondrial morphogenesis, dendrite development, andsynapse formation in cerebellum require both Bcl-w and the glutamate receptor delta2.PLoS Genet.6:e1000097.
21. Yoon Y, et al.(2003) The mitochondrial protein hFis1regulates mitochondrial fissionin mammalian cells through an interaction with the dynamin-like protein DLP1. MolCell Biol.15:p.5409-5420.
22. Stojanovski D, et al.(2004) Levels of human Fis1at the mitochondrial outer membraneregulate mitochondrial morphology. J Cell Sci.7:p.1201-1210.
23. Madhavika N，Serasinghe， Yisang Yoon.(2008) The mitochondrial outer membraneprotein hFis1regulates mitochondrial morphology and fission through self-interaction.Exp Cell Res.19: p.3494-3507.
24. Robert CW, et al.(2007) Direct Binding of the Dynamin-like GTPase, Dnm1,tomitochondrial Dynamics Protein Fis1is Negatively Regulated by the Fis1,N-terminalArm. J Biol Chem.46: p.33769-33775.
25. Lee YJ, et al.(2004) Roles of the mammalian mitochondrial fission and fusionmediators Fis1, Drp1, and Opa1in apoptosis. Mol Biol Cell.15: p.5001-5011.
26. Wasiak S, Zunino R, McBride HM.(2007) Bax/Bak promote sumoylation of DRP1and its stable association with mitochondria during apoptotic cell death. J Cell Biol.177: p.439-450.
27. Hidenori Otera, Chunxin Wang, Megan M.(2010) Mff is an essential factor formitochondrial recruitment of Drp1during mitochondrial fission in mammalian cells. JCell Biol.6: p.1141–1158.
28. Benard G, et al.(2007) Mitochondrial bioenergetics and structural networkorganization. J. Cell Sci.120: p.838-848
29. Philippe A. et al.(2008) Preventing Mitochondrial Fission Impairs MitochondrialFunction and Leads to Loss of Mitochondrial DNA. PLOS ONE. e3257: p.1-9
30. Adriana Malena, et al.(2009) Inhibition of Mitochondrial Fission Favours Mutant OverWild-type Mitochondrial DNA. Hum Mol Genet.18: p.3407-3416.
31. Gilad Twig, et al.(2008) Fission and selective fusion govern mitochondrial segregationand elimination by autophagy. EMBO J.27: p.433–446.
32. Seungmin Lee, et al.(2007) Mitochondrial Fission and Fusion Mediators, hFis1andOPA1,Modulate Cellular Senescence. J Biol Chem.282: p.22977–22983.
33. Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J.(2009) A hyperfusedmitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase.Proc NatlAcad Sci U SA.106(29): p.11960-11965.
34. Santel A, Fuller M.(2001) Control of mitochondrial morphology by a human mitofusin.J Cell Sci.114: p.867-874
35. Koshiba T, et al.(2004) Structural basis of mitochondrial tethering by mitofusincomplexes acting in trans. Science.305: p.858–862.
36. Ishihara N, Eura Y, and Mihara K.(2004) Mitofusin1and2play distinct roles inmitochondrial fusion reactions via GTPase activity. J Cell Sci.117: p.6535–6546.
37. Bourne HR, Sanders DA, McCormick F.(1991) The GTPase superfamily: conservedstructure and molecular mechanism. Nature.349(6305): p.117-127.
38. Chen H, et al.(2003) Mitofusins Mfn1and Mfn2coordinately regulate mitochondrialfusion and are essential for embryonic development. J Cell Biol.160(2): p.189-200.
39. de Brito OM, Scorrano L.(2008) Mitofusin2tethers endoplasmic reticulum tomitochondria. Nature.456(7222): p.605-610
40. Rojo M, Legros F, Chateau D, Lomebs A.(2002) Membrane topology andmitochondrial targeting of mitofusins, ubiquitous mammalian homologues of thetransmembrane GTPase Fzo. J Cell Sci.115: p.1663-1674.
41. Delettre C, et al.(2001) Mutation spectrum and splicing variants in the OPA1gene.Hum Genet,109: p.584–591.
42. Satoh M, Hamamoto T, Seo N, Kagawa Y. and Endo H.(2003) Differentialsublocalization of the dynamin-related protein OPA1isoforms in mitochondria.Biochem Biophy Res Commun.300: p.482–493.
43. Frezza C, et al.(2006) OPA1controls apoptototic cristae remoding independently frommitochondrial fusion. Cell.126: p.177-189.
44. Meeusen S, et al.(2006) Mitochondrial inner-membrane fusion and crista maintenancerequires the dynamin-related GTPase Mgm1. Cell.127(2): p.383-395.
45. Sesaki H, Jensen RE.(2004) Ugo1p links the Fzo1p and Mgm1p GTPases formitochondrial fusion. J Biol Chem.279(27): p.28298-28303.
46. Shelly Meeusen J，et al.(2004) Mitochondrial Fusion Intermediates Revealed in Vitro.Science.17: p.1747-1752.
47. Legros F, Lombes A,43. Frachon P, Rojo M.(2002) Mitochondrial fusion in humancell is efficient, requires inner membrane potential and Mitofusin. Mol Biol Cell.13: p.4343-4354.
48. Malka F, et al.(2005) Separate fusion of outer and inner mitochondrial membranes.EMBO Rep.6(9): p.853-859.
49. Zhiyin Song, et al.(2009) Mitofusins and OPA1Mediate Sequential Steps inMitochondrial Membrane Fusion. Mol Biol Cell.20(15): p.3525-3532.
50. Cohen MM, et al.(2008) Ubiquitin-Proteasmome-dependent degradation of amitofusion, a critical regulator of mitochondrial fusion. Mol Biol Cell.19: p.2454-2464.
51. Noriyuki Matsuda, et al.(2010) PINK1stabilized by mitochondrial depolarizationrecruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. JCell Biol.189: p.211-221.
52. Matthew EG, J Mark Cooper (2010) Mitofusin1and Mitofusin2are ubiquitinated in aPINK1parkin dependent manner upon mitophagy. Hum Mol Genet.19(24): p.4861-4870.
53. Guillery O, et al.(2008) Metalloprotease-mediated OPA1processing is modulated bythe mitochondrial membrane potential. M Biol Cell.100(5): p.315-325.
54. McQuibban GA, Saurya S, Freeman M.(2003) Mitochondrial membrane remodellingregulated by a conserved rhomboid protease. Nature.423(6939): p.537-541.
55. Ehses S, Raschke I, Mancuso G,(2009) Regulation of OPA1processing andmitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol.187(7):p.1023-1036.
56. Hsiuchen Chen, et al.(2010) Mitochondrial Fusion Is Required for mtDNA Stability inSkeletal Muscle and Tolerance of mtDNA Mutations. Cell.141: p.280–289.
57. Daniel Tondera, et al.(2009) SLP-2is required for stress-induced mitochondrialhyperfusion. The EMBO Journal.28: p.1589–1600.
58. Angelika S. Rambold, Brenda Kostelecky, Natalie Elia, and JenniferLippincott-Schwartz.(2011).Tubular network formation protects mitochondria fromautophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A.108(25): p.10190-10195.
59. Mariusz Karbowski, Seon-Yong Jeong, Richard J. Youle.(2004) Endophilin B1isrequired for the maintenance of mitochondrial morphology. J Cell Biol.166(7): p.1027-1039.
60. Arnoult D, et al.(2005) Bax/Bak-dependent release of DDP/TIMM8a promotesDrp1-mediated mitochondrial fission and mitoptosis during programmed cell death.Curr Biol.15(23): p.2112-2118.
61. Niemann A, Ruegg M, La Padula V, Schenone A, Suter U.(2005) Ganglioside-induceddifferentiation associated protein1is a regulator of the mitochondrial network: newimplications for Charcot-Marie-Tooth disease. J Cell Biol.170(7): p.1067-1078.
62. Wagner KM, Rüegg M, Niemann A, Suter U.(2009) Targeting and function of themitochondrial fission factor GDAP1are dependent on its tail-anchor. PLoS One.4(4):e5160.
63. Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S.(2006) MARCH-V is a novelmitofusin2-and Drp1-binding protein able to change mitochondrial morphology.EMBO Rep.7(10): p.1019-1022.
64. Karbowski M, Neutzner A, Youle RJ.(2007) The mitochondrial E3ubiquitin ligaseMARCH5is required for Drp1dependent mitochondrial division. J Cell Biol.178(1): p.71-84.
65. Park YY, Lee S, Karbowski M, Neutzner A, Youle RJ, Cho H.(2010) Loss ofMARCH5mitochondrial E3ubiquitin ligase induces cellular senescence throughdynamin-related protein1and mitofusin1. J Cell Sci.123(Pt4): p.619-626.
66. Gandre-Babbe S and AM van der Bliek (2008) The novel tail-anchored membraneprotein Mff controls mitochondrial and peroxisomal fission in mammalian cells. MolBiol Cell.19(6): p.2402-2412.
67. Parcellier A, et al.(2009) The Carboxy-Terminal Modulator Protein (CTMP) regulatesmitochondrial dynamics. PLoS One.4(5): p. e5471.
68. Aihara T, et al.(2009) A novel potential role for gametogenetin-binding protein1(GGNBP1) in mitochondrial morphogenesis during spermatogenesis in mice. BiolReprod.80(4): p.762-770.
69. Choi SY, et al.(2006) A common lipid links Mfn-mediated mitochondrial fusion andSNARE-regulated exocytosis. Nat Cell Biol.8(11): p.1255-1262.
70. Huang, H. and M.A. Frohman,(2009) Lipid signaling on the mitochondrial surface.Biochim Biophys Acta.1791(9): p.839-844.
71. Li J, et al.(2012) Lysocardiolipin acyltransferase1(ALCAT1) controls mitochondrialDNA fidelity and biogenesis through modulation of MFN2expression. Proc Natl AcadSci U S A. May1;109(18):6975-6980. Epub2012Apr16.
72. Eura Y, et al.(2006) Identification of a novel protein that regulates mitochondrialfusion by modulating mitofusin (Mfn) protein function. J Cell Sci.119(Pt23): p.4913-4925.
73. Zhao J, et al.(2011) Human MIEF1recruits Drp1to mitochondrial outer membranesand promotes mitochondrial fusion rather than fission. EMBO J.30(14): p.2762-2778.
74. Liesa M, et al.(2008) Mitochondrial fusion is increased by the nuclear coactivatorPGC-1beta. PLoS One.3(10): p. e3613.
75. Wang K, et al.(2012) miR-484regulates mitochondrial network through targeting Fis1.Nat Commun.3: p.781.
76. Frank S, et al.(2001) The role of dynamin-related protein1, a mediator ofmitochondrial fission, in apoptosis. Dev Cell.1(4): p.515-525.
77. James DI, et al.(2003) hFis1, a novel component of the mammalian mitochondrialfission machinery. J Biol Chem.278(38): p.36373-36379.
78. Sugioka R, S Shimizu and Y Tsujimoto.(2004) nFzo1, a protein involved inmitochondrial fusion, inhibits apoptosis. J Biol Chem.279(50): p.52726-52734.
79. Olichon A, et al.(2003) Loss of OPA1perturbates the mitochondrial inner membranestructure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem.278(10): p.7743-7746.
80. Karbowski M, et al.(2002) Spatial and temporal association of Bax with mitochondrialfission sites, Drp1, and Mfn2during apoptosis. J Cell Biol.159(6): p.931-938.
81. Neuspiel M, et al.(2005) Activated mitofusin2signals mitochondrial fusion, interfereswith Bax activation, and reduces susceptibility to radical induced depolarization. J BiolChem.280(26): p.25060-25070.
82. Sheridan C, et al.(2008) Bax-or Bak-induced mitochondrial fission can be uncoupledfrom cytochrome C release. Mol Cell.31(4): p.570-585.
83. Hom JR, et al.(2007) Thapsigargin induces biphasic fragmentation of mitochondriathrough calcium-mediated mitochondrial fission and apoptosis. J Cell Physiol.212(2):p.498-508.
84. Alirol E, et al.(2006) The mitochondrial fission protein hFis1requires the endoplasmicreticulum gateway to induce apoptosis. Mol Biol Cell.17(11): p.4593-4605.
85. Parone PA, et al.,(2006) Inhibiting the mitochondrial fission machinery does notprevent Bax/Bak-dependent apoptosis. Mol Cell Biol.26(20): p.7397-7408.
86. Chen H, et al.(2003) Mitofusins Mfn1and Mfn2coordinately regulate mitochondrialfusion and are essential for embryonic development. J Cell Biol.160(2): p.189-200.
87. Chen H, A Chomyn and DC Chan,(2005) Disruption of fusion results in mitochondrialheterogeneity and dysfunction. J Biol Chem.280(28): p.26185-26192.
88. Hirai K, et al.(2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci.21(9): p.3017-3023.
89. Wang X, et al.(2008) Dynamin-like protein1reduction underlies mitochondrialmorphology and distribution abnormalities in fibroblasts from sporadic Alzheimer'sdisease patients. Am J Pathol.173(2): p.470-482.
90. Wang X, et al.(2009) Impaired balance of mitochondrial fission and fusion inAlzheimer's disease. J Neurosci.29(28): p.9090-9103.
91. Manczak M, MJ Calkins and PH Reddy (2011) Impaired mitochondrial dynamics andabnormal interaction of amyloid beta with mitochondrial protein Drp1in neurons frompatients with Alzheimer's disease: implications for neuronal damage. Hum Mol Genet.20(13): p.2495-2509.
92. Tatebayashi Y, et al.(2004) Role of tau phosphorylation by glycogen synthasekinase-3beta in the regulation of organelle transport. J Cell Sci.117(Pt9): p.1653-1663.
93. Shahpasand K, et al.(2012) Regulation of mitochondrial transport andinter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated inAlzheimer's disease. J Neurosci.32(7):2430-2441.
94. Kanaan NM, et al.(2012) Phosphorylation in the amino terminus of tau preventsinhibition of anterograde axonal transport. Neurobiol Aging.33(4): p.826.e15-30
95. Quintanilla RA, et al.(2009) Caspase-cleaved tau expression induces mitochondrialdysfunction in immortalized cortical neurons: implications for the pathogenesis ofAlzheimer disease. J Biol Chem.284(28): p.18754-18766.
96. Amadoro G, et al.(2010) A NH2tau fragment targets neuronal mitochondria at ADsynapses: possible I implications for neurodegeneration. J Alzheimers Dis.21(2): p.445-470.
97. Rhein V, et al.(2009) Amyloid-beta and tau synergistically impair the oxidativephosphorylation system in triple transgenic Alzheimer's disease mice. Proc Natl AcadSci U S A.106(47): p.20057-20062.
98. Kopeikina KJ, et al.(2011) Tau accumulation causes mitochondrial distributiondeficits in neurons in a mouse model of tauopathy and in human Alzheimer's diseasebrain. Am J Pathol.179(4): p.2071-2082.
99. Manczak M, Reddy PH.(2012) Abnormal interaction between the mitochondrialfission protein Drp1and hyperphosphorylated tau in Alzheimer's disease neurons:implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet.Mar13.[Epub ahead of print].
100.Manczak M, Sesaki H, Kageyama Y, Reddy PH.(2012) Dynamin-related protein1heterozygote knockout mice do not have synaptic and mitochondrial deficiencies.Biochim BiophysActa.1822(6):862-874. Epub2012Feb23.
101.A Atlante, et al.(2008) A peptide containing residues26–44of tau protein impairsmitochondrial oxidative phosphorylation acting at the level of the adenine nucleotidetranslocator. Biochim BiophysActa.1777(10):1289-300.
102.Cristian ALR, et al.(2011) Tau oligomers impair memory and induce synaptic andmitochondrial dysfunction in wild-type mice. Mol Neurodegeneration.6:39.
2. Grundke-Iqbal I, et al.(1986) Microtubule-associated protein tau: A component ofAlzheimer paired helical filaments. J Biol Chem.261:6084–6089.
3. Iqbal K, et al.(1989) Identification and localization of a tau peptide to paired helicalfilaments of Alzheimer disease. Proc Natl Acad Sci USA.86:5646-5650.
4. Berger Z, et al.(2007) Accumulation of pathological tau species and memory loss in aconditional model of tauopathy. J Neurosci.27(14): p.3650-3662.
5. Andorfer C, et al.（2003）Hyperphosphorylation and aggregation of tau in miceexpressing normal human tau isoforms. J Neurochem.86(3): p.582-590.
6. Boutajangout A, D Quartermain and EM Sigurdsson (2010) Immunotherapy targetingpathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci.30(49): p.16559-16566.
7. Van der Jeugd A, et al.（2011） Hippocampal tauopathy in tau transgenic micecoincides with impaired hippocampus-dependent learning and memory, and attenuatedlate-phase long-term depression of synaptic transmission. Neurobiol Learn Mem.95(3): p.296-304.
8. Benard, G. and M. Karbowski.(2009) Mitochondrial fusion and division: Regulationand role in cell viability. Semin Cell Dev Biol.20(3): p.365-374.
9. Chen H and DC Chan (2009) Mitochondrial dynamics--fusion, fission, movement, andmitophagy--in neurodegenerative diseases. Hum Mol Genet.18(R2): p. R169-176.
10. Smirnova E, et al.(2001) Dynamin-related protein Drp1is required for mitochondrialdivision in mammalian cells. Mol Biol Cell,12(8): p.2245-2256.
11. James DI, et al.(2003) hFis1, a novel component of the mammalian mitochondrialfission machinery. J Biol Chem.278(38): p.36373-36379.
12. Wells RC, et al.(2007) Direct binding of the dynamin-like GTPase, Dnm1, tomitochondrial dynamics protein Fis1is negatively regulated by the Fis1N-terminalarm. J Biol Chem.282(46): p.33769-33775.
13. Suzuki M, et al.(2003) The solution structure of human mitochondria fission proteinFis1reveals a novel TPR-like helix bundle. J Mol Biol.334(3): p.445-458.
14. Santel A. and MT Fuller.（2001） Control of mitochondrial morphology by a humanmitofusin. J Cell Sci.114(Pt5): p.867-874.
15. Rojo M, et al.（2002）Membrane topology and mitochondrial targeting of mitofusins,ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci.115(Pt8): p.1663-1674
16Chen H, A Chomyn and DC Chan.(2005) Disruption of fusion results inmitochondrial heterogeneity and dysfunction. J Biol Chem.280(28): p.26185-26192.
17. Frezza C, et al.(2006) OPA1controls apoptotic cristae remodeling independentlyfrom mitochondrial fusion. Cell.126(1): p.177-189.
18. Cipolat S, et al.(2004) OPA1requires mitofusin1to promote mitochondrial fusion.Proc Natl Acad Sci U S A.101(45): p.15927-15932.
19. Chen H, et al.(2010) Mitochondrial fusion is required for mtDNA stability in skeletalmuscle and tolerance of mtDNA mutations. Cell.141(2): p.280-289.
20. Pellegrini L. and L Scorrano.(2007) A cut short to death: Parl and Opa1in theregulation of mitochondrial morphology and apoptosis. Cell Death Differ.14(7): p.1275-1284.
21. Jahani-Asl A, et al.(2011) The mitochondrial inner membrane GTPase, optic atrophy1(Opa1), restores mitochondrial morphology and promotes neuronal survivalfollowing excitotoxicity. J Biol Chem.286(6): p.4772-4782.
22. Twig G, et al.(2008) Fission and selective fusion govern mitochondrial segregation andelimination by autophagy. EMBO J.27(2): p.433-446.
23. Karbowski M, et al.(2002) Spatial and temporal association of Bax withmitochondrial fission sites, Drp1, and Mfn2during apoptosis. J Cell Biol.159(6): p.931-938.
24. Wang X, et al.(2008) Amyloid-beta overproduction causes abnormal mitochondrialdynamics via differential modulation of mitochondrial fission/fusion proteins. ProcNatl Acad Sci U S A.105(49): p.19318-19323.
25. Wang X, et al.(2009) Impaired balance of mitochondrial fission and fusion inAlzheimer's disease. J Neurosci.29(28): p.9090-9103.
26. Rhein V, et al.(2009) Amyloid-beta and tau synergistically impair the oxidativephosphorylation system in triple transgenic Alzheimer's disease mice. Proc NatlAcad Sci U S A.106(47): p.20057-20062.
27. David DC, et al.(2005) Proteomic and functional analyses reveal a mitochondrialdysfunction in P301L tau transgenic mice. J Biol Chem.280(25): p.23802-23814.
28. Kopeikina KJ, et al.(2011) Tau accumulation causes mitochondrial distributiondeficits in neurons in a mouse model of tauopathy and in human Alzheimer's diseasebrain. Am J Pathol.179(4): p.2071-2082.
29. Quintanilla RA, et al.(2009) Caspase-cleaved tau expression induces mitochondrialdysfunction in immortalized cortical neurons: implications for the pathogenesis ofAlzheimer disease. J Biol Chem.284(28): p.18754-18766.
30. Amadoro G, et al.（2010） A NH2tau fragment targets neuronal mitochondria at ADsynapses: possible implications for neurodegeneration. J Alzheimers Dis.21(2): p.445-470.
31. Li HL, et al.(2007) Phosphorylation of tau antagonizes apoptosis by stabilizingbeta-catenin, a mechanism involved in Alzheimer's neurodegeneration. Proc NatlAcad Sci U S A.104(9): p.3591-6.
32. Wang ZF, et al.(2010) Overexpression of tau proteins antagonizesamyloid-beta-potentiated apoptosis through mitochondria-caspase-3pathway in N2acells. J Alzheimers Dis.20(1): p.145-57.
33. Erturk A, et al.(2007) Disorganized microtubules underlie the formation of retractionbulbs and the failure of axonal regeneration. J Neurosci.27(34): p.9169-80.
34. Gandhi S, et al.(2006) PINK1protein in normal human brain and Parkinson's disease.Brain.129(Pt7): p.1720-31.
35. Song Z, et al.(2009) Mitofusins and OPA1mediate sequential steps in mitochondrialmembrane fusion. Mol Biol Cell.20(15): p.3525-32.
36. Cohen MM, et al.(2008) Ubiquitin-proteasome-dependent degradation of a mitofusin,a critical regulator of mitochondrial fusion. Mol Biol Cell.19(6): p.2457-64.
37Matsuda N, et al.(2010) PINK1stabilized by mitochondrial depolarization recruitsParkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol.189(2): p.211-21.
38Nickie C Chan, et al.(2011) Broad activation of ubiquitin proteasome system byparkin is critical for mitophagy. Hum Mol Genet.20(9): p.1726-1737.
39. Atsushi Tanaka, et al.(2011) Proteasome and P97mediate mitophagy and degradationof mitofusins induced by parkin. J Cell Biol.191: p.1367-1380.
40Sorokin AV, Kim ER, Ovchinnikov LP.(2009) Proteasome system of proteindegradation and processing. Biochemistry (Mosc).74: p.1411-1442.
41. Arriagada PV, et al.（1992） Neurofibrillary tangles but not senile plaques parallelduration and severity of Alzheimer's disease. Neurology.42(3Pt1): p.631-639.
42. Hirai K, et al.(2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci.21(9): p.3017-3023.
43. de Calignon A, et al.(2010) Caspase activation precedes and leads to tangles. Nature.464:1201-1204.
44. Tondera D, et al.(2009) SLP-2is required for stress-induced mitochondrialhyperfusion. EMBO J.28(11): p.1589-600.
45LaPointe NE, et al.(2009) The amino terminus of tau inhibits kinesin-dependentaxonal transport: implications for filament toxicity. J Neurosci Res.87(2): p.440-451.
46Dixit R, Ross JL, Goldman YE, Holzbaur EL.(2008) Differential regulation of dyneinand kinesin motor proteins by tau. Science.319(5866):p.1086-1089.
47Misko A, et al.(2010) Mitofusin2is necessary for transport of axonal mitochondriaand interacts with the Miro/Milton complex. J Neurosci.30(12): p.4232-4240.
48. Glauser L, et al.（2011）Parkin promotes the ubiquitination and degradation of themitochondrial fusion factor mitofusin1. J Neurochem.118(4): p.636-645.
49Haque ME, et al.(2008) Cytoplasmic Pink1activity protects neurons fromdopaminergic neurotoxin MPTP. Proc Natl Acad Sci U S A.105(5): p.1716-1721.
50Zhou C, et al.(2008) The kinase domain of mitochondrial PINK1faces the cytoplasm.Proc Natl Acad Sci U S A.105(33): p.12022-7.
51Wilhelmus MM, et al.(2011) Association of Parkinson disease-related protein PINK1with Alzheimer disease and multiple sclerosis brain lesions. Free Radic Biol Med.50(3): p.469-76.
52Canu N, Filesi I, Pristerà A, Ciotti MT, Biocca S (2011) Altered IntracellularDistribution of PrPC and Impairment of Proteasome Activity in Tau OverexpressingCortical Neurons. J Alzheimers Dis27: p.603-613.
53Mandelkow EM, et al.（1996） Structure, microtubule interactions, andphosphorylation of tau protein. Ann N Y Acad Sci. Jan17;777:96-106.
54Andorfer C, et al.(2003) Hyperphosphorylation and aggregation of tau in miceexpressing normal human tau isoforms. J Neurochem.86(3):p.582-590.
55Andorfer C, et al.(2005) Cell-cycle reentry and cell death in transgenic miceexpressing nonmutant human tau isoforms. J Neurosci.25(22): p.5446-5454.
56Ando K,et al.(2011) Accelerated human mutant tau aggregation by knocking outmurine tau in a transgenic mouse model. Am J Pathol.178(2): p.803-816.
57Shahpasand K, et al.(2012) Regulation of mitochondrial transport andinter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated inAlzheimer's disease. J Neurosci.32(7):p.2430-2441.
58Poorki P, et al.(2001) A genomic sequence analysis of the mouse and humanmicrotubule-associated protein tau. Mamm Genome.12:700-712.
59Cristian ALR, Diana LCC, Urmi S, et al.(2011) Tau oligomers impair memory andinduce synaptic and mitochondrial dysfunction in wild-type mice. MolNeurodegeneration. Jun6;6:39.
60. Li Q, et al.(2010) ALS-linked mutant superoxide dismutase1(SOD1) altersmitochondrial protein composition and decreases protein import. Proc Natl Acad Sci US A107:21146-21151
61Kimura T, et al.（2010）Aggregation of detergent-insoluble tau is involved in neuronalloss but not in synaptic loss. J Biol Chem.285(49): p.38692-386999.
1I. Grundke-Iqbal, K. Iqbal, M. Quinlan, Y.C. Tung, M.S. Zaidi, H.M. Wisniewski,Microtubule-associated protein tau: a component of Alzheimer paired helical filament,J. Biol. Chem.261(1986)6084-6089.
2V.M. Lee, B.J. Balin, L.J. Otvos, J.Q. Trojanowski, A68: a major subunit of the pairedhelical filaments and derivatized forms of normal tau, Science251(1991)675-678.
3C.X. Gong, T. Lidsky, J. Wegiel, L. Zuck, I. Grundke-Iqbal, K. Iqbal, Phosphorylationof microtubule-associated protein tau is regulated by protein phosphatase2A inmammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease,J. Biol. Chem.275(2000)5535-5544.
4F. Liu, I. Grundke-Iqbal, K. Iqbal, C.X. Gong, Contributions of protein phosphatasesPP1, PP2A, PP2B and PP5to the regulation of tau phosphorylation, Eur. J. Neurosci.22(2005)1942-1950.
5E. Planel, K. Yasutake, S.C. Fujita, K. Ishiguro, Inhibition of phosphatase2Aoverridestau protein kinase1/glycogen synthase kinase3and cyclin-dependent kinase5inhibition and results in tau hyperphosphorylation in the hippocampus of starvedmouse, J. Biol. Chem.276(2000)34298-34306.
6A. Takashima, GSK-3is essential in the pathogenesis of Alzheimer’s disease, J.Alzheimers Dis.9(2006)309-317.
7J.Avila, J.Dí az-Nido, Tangling with hypothermia, Nat. Med.10(2004)460-461.
8J.Z. Wang, C.X. Gong, T. Zaidi, I. Grundke-Iqbal, K. Iqbal, Dephosphorylation ofAlzheimer paired helical filaments by protein phosphatase-2A and-2B, J. Biol. Chem.270(1995)4854-4860.
9A. Takashima, K. Noguchi, G. Michel, M. Mercken, M. Hoshi, K. Ishiguro, K.Imahori, Exposure of rat hippocampal neurons to amyloid beta peptide (25–35)induces the inactivation of phosphatidyl inositol-3kinase and the activation of tauprotein kinase I/glycogen synthase kinase-3beta, Neurosci. Lett.203(1996)33-36.
10K. Ishiquro, A. Shiratsuchi, S. Sato, A. Omori, M. Arioka, S. Kobayashi, T. Uchida, K.Imahori, Glycogen synthase kinase3beta is identical to tau protein kinase I generatingseveral epitopes of paired helical flaments, FEBS Lett.325(1993)167-172.
11D.P. Hanger, B.H. Anderton, W. Noble, Tau phosphorylation: the therapeutic challengefor neurodegenerative disease, Trends Mol. Med.15(2009)112-119.
12] J. Z. Wang, F. Liu, Microtubule-associated protein tau in development,degeneration and protection of neurons, Prog. Neurobiol.85(2008)148-175.
13S. Lovestone, C.H. Reynolds, D. Latimer, D.R. Davis, B.H. Anderton, J.M. Gallo, D.Hanger, S. Mulot, B. Marquardt, S. Stabel, et al., Alzheimer’s disease-likephosphorylation of the microtubule-associated protein tau by glycogen synthasekinase-3in transfected mammalian cells, Curr. Biol.4(1994)1077-1086.
14J.R. Munoz-Montano, F.J. Moreno, J. Avila, J. Diaz-Nido, Lithium inhibitsAlzheimer’s disease-like tau protein phosphorylation in neurons, FEBS Lett.411(1997)183-188.
15M. Hong, D.C. Chen, P.S. Klein, V.M. Lee, Lithium reduces tau phosphorylation byinhibition of glycogen synthase kinase-3, J. Biol. Chem.272(1997)25326-25332.
16S.J. Liu, A.H. Zhang, H.L. Li, O. Wang, H.M. Deng, W.J. Netzer, H.X. Xu, J.Z. Wang,Overactivation of glycogen synthase kinase-3by inhibition of phosphoinositol-3kinase and protein kinase C leads to hyperphosphorylation of tau and impairment ofspatial memory, J. Neurochem.87(2003)1333-1344.
17I. Ferrer, M. Barrachina, B. Puig, Glycogen synthase kinase-3is associated withneuronal and glial hyperphosphorylated tau deposits in Alzheimer’s disease, Pick’sdisease, progressive supranuclear palsy and corticobasal degeneration, Acta.Neuropathol.(Berl)104(2002)583-591.
18J.J. Pei, E. Braak, H. Braak, I. Grundke-Iqbal, K. Iqbal, B. Winblad, R.F. Cowburn,Distribution of active glycogen synthase kinase3(GSK-3) in brains staged forAlzheimer disease neurofbrillary changes, J. Neuropathol. Exp. Neurol.58(1999)1010-1019.
19J.J. Lucas, F. Hernández, P. Gómez-Ramos, M.A. Morán, R. Hen, J. Avila,Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration inGSK-3beta conditional transgenic mice, EMBO J.20(2001)27-39.
20C.X. Gong, T.J. Singh, I. Grundke-Iqbal, K. Iqbal, Phosphoprotein phosphataseactivities inAlzheimer disease brain, J. Neurochem.61(1993)921-927.
21J.Z. Wang, I. Grundke-Iqbal, K. Iqbal, Tau is phosphorylated by GSK-3at several sitesfound in AD and its biological activity markedly inhibited only after it isprephosphorylated byA-kinase, FEBS Lett.436(1998)28-34.
22J.Z. Wang, I. Grundke-Iqbal, K. Iqbal, Kinases and phosphatases and tau sites nvolvedinAlzheimer neurofibrillary degeneration, Eur. J. Neurosci.25(2007)59-68.
23L. Sun, S.Y. Liu, X.W. Zhou, X.C. Wang, R. Liu, Q. Wang, J.Z. Wang, Inhibition ofprotein phosphatase2a-and protein phosphatase1-induced tau hyperphosphorylationand impairment of spatial memory retention in rats, Neuroscience118(2003)1175-1182.
24Q. Tian, Z.Q. Lin, X.C. Wang, J. Chen, Q. Wang, C.X. Gong, J.Z. Wang, Injection ofokadaic acid into the meynert nucleus basalis of rat brain induces decreasedacetylcholine level and spatial memory deficit, Neuroscience126(2004)277-184.
25M. Li, H. Guo, Z. Damuni, Purification and characterization of two potent heat-stableprotein inhibitors of protein phosphatase2A from bovine kidney, Biochemistry34(1995)1988-1996.
26I. Tsujio, T. Zaidi, J. Xu, L. Kotula, I. Grundke-Iqbal,K. Iqbal, Inhibitors of proteinphosphatase-2A from human brain structures, immunocytological localization andactivities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau,FEBS Lett.579(2005)363-372.
27H. Tanimukai, I. Grundke-Iqbal, K. Iqbal, Upregulation of inhibitors of proteinphosphatase-2A in Alzheimer’s disease, Am. J. Pathol.166(2005)1761-1771.
28G.P. Liu, Y. Zhang, X.Q. Yao, C.E. Zhang, J. Fang, Q. Wang, J.Z. Wang, Activation ofglycogen synthase kinase-3inhibits protein phosphatase-2A and the underlyingmechanisms, Neurobiol.Aging29(2008)1348-1358.
29J.P. ten Klooster, I. Leeuwen, N. Scheres, E.C. Anthony, P.L. Hordijk, Rac1-inducedcell migration requires membrane recruitment of the nuclear oncogene SET, EMBO J.26(2007)336-345.
30T.R. Brummelkamp, R. Bernards, R. Agami, A system for stable expression of shortinterfering RNAs in mammalian cells, Science296(2002)550-553.
31S.M. Elbashir, J. Harborth, W. Lendeckel, A. Yalcin, K. Weber, T. Tuschl, Duplexesof21-nucleotide RNAs mediate RNA interference in cultured mammalian cells,Nature411(2001)494-498.
32L. Naldini, U. Bl mer, P. Gallay, D. Ory, R. Mulligan, F.H. Gage, I.M. Verma, D.Trono, In vivo gene delivery and stable transduction of nondividing cells by alentiviral vector, Science272(1996)263-267.
33R.A. Marr, E. Rockenstein, A. Mukherjee, M.S. Kindy, L.B. Hersh, F.H. Gage, I.M.Verma, E. Masliah, Neprilysin gene transfer reduces human amyloid pathology intransgenic mice, J. Neurosci.23(2003)1992-1996.
34M. Polydoro, C.M. Acker, K. Duff, P.E. Castillo, P. Davies, Age-dependentimpairment of cognitive and synaptic function in the htau mouse model of taupathology, J Neurosci.29(2009)10741-10749.
35B.K. Kaspar, B. Vissel, T. Bengoechea, S. Crone, L. Randolph-Moore, R. Muller, E.P.Brandon, D. Schaffer, I.M. Verma, K.F. Lee, S.F. Heinemann, F.H. Gage,Adeno-associated virus effectively mediates conditional gene modification in the brain,Proc. Natl.Acad. Sci. USA99(2002)2320-2325.
36M.R. Zarrindast, M. Bananej, A. Khalilzadeh, S. Fazli-Tabaei, A. Haeri-Rohani, A.Rezayof, Influence of intracerebroventricular administration of dopaminergic drugs onmorphine state-dependent memory in the step-down passive avoidance test. Neurobiol.Learn Mem.86(2006)286-292.
37C.S. Woolley, B.S. McEwen, Estradiol mediates fluctuation in hippocampal synapsedensity during the estrous cycle in the adult rat. J Neurosci12(1992)2549-2554.
38M. Li, A. Makkinje, Z. Damuni, The myeloid leukemia-associated protein SET is apotent inhibitor of protein phosphatase2A, J. Biol. Chem.271(1996)11059-11062.
39G.P. Liu, W. Wei, X. Zhou, Y. Zhang, H.H. Shi, J. Yin, X.Q. Yao, C.X. Peng, J. Hu, Q.Wang, H.L. Li, J.Z. Wang, I(2)(PP2A) regulates p53and Akt correlatively and leadsthe neurons to abort apoptosis, Neurobiol. Aging33(2012)254-264.
40D.A. Cross, D.R. Alessi, P. Cohen, M. Andjelkovich, B.A. Hemmings, Inhibition ofglycogen synthase kinase-3by insulin mediated by protein kinase B, Nature378(1995)785-789.
41M. Shaw, P. Cohen, D.R. Alessi, Further evidence that the inhibition of glycogensynthase kinase-3beta by IGF-1is mediated by PDK1/PKB-induced phosphorylationof Ser-9and not by dephosphorylation of Tyr-216, FEBS Lett.416(1997)307-311.
42X. Fang, S.X. Yu, Y. Lu, Jr. Bast RC, J.R. Woodgett, G.B. Mills, Phosphorylationand inactivation of glycogen synthase kinase3by protein kinase A, Proc. Natl. Acad.Sci. USA97(2000)11960-11965.
43X. Wang, J. Blanchard, E. Kohlbrenner, N. Clement, R.M. Linden, A. Radu, I.Grundke-Iqbal, K. Iqbal, The carboxy-terminal fragment of inhibitor-2of proteinphosphatase-2A induces Alzheimer disease pathology and cognitive impairment,FASEB J.24(2010)4420-4432.
44S. Peineau, C. Taqhibiglou, T.P. Wonq, L. Liu, J. Lu, E. Lo, D. Wu, E. Saule, T.Bouschet, P. Matthews, J.T. Isaac, Z.A. Bortolotto, Y.T. Wang, G.L. Collinqridge, LTPinhibits LTD in the hippocampus via regulation of GSK-3beta, Neuron53(2007)703-717.
45T. Kimura, S. Yamashhita, S. Nakao, J.M. Park, M. Murayama, T. Mizoroki, Y.Yoshiike, N. Sahara, A. Takashima, GSK-3beta is required for memory reconsolidationin adult brain, PLos One3(2008) e3540.
46T. Engel, F. Hernández, J. Avila, J.J. Lucas, Full reversal of Alzheimer’s disease-likephenotype in a mouse model with conditional overexpression of glycogen synthasekinase-3, J. Neurosci.26(2006)5083-5090.
47E.S. Emamian, D. Hall, M.J. Birnbaum, M. Krayiorou, J.A. Goqos, Convergentevidence for impaired AKT1-GSK-3beta signaling in schizophrenia, Nat. Genet.6(2004)131-137.
48K. Leroy, Z. Yilmaz, J.P. Brion, Increase level of active GSK-3β in Alzheimer’sdisease and accumulation in argyrophilic grains and in neurons at different stages ofneurofibrillary degeneration, Neuropathol. Appl. Neurobiol.33(2007)43-55.
49A. Hye, F. Kerr, N. Archer, C. Foy, M. Poppe, R. Brown, G. Hamilton, J. Powell, B.Anderton, S. Lovestone, Glycogen synthase kinase-3is increased in white cells earlyAlzheimer’s disease, Neurosci. Lett.373(2005)1-4.
50A.E. Aplin, G.M. Gibb, J.S. Jacobsen, J.M. Gallo, B.H. Anderton, In vitrophosphorylation of the cytoplasmic domain of the amyloid precursor protein byglycogen synthase kinase-3, J. Neurochem.67(1996)699-707.
51A. Takashima, K. Noguchi, K. Sato, T. Hoshino, K. Imahori, Tau protein kinase I isessential for amyloid-protein-induced neurotoxicity, Proc. Natl. Acad. Sci. USA90(1993)7789-7793.
52A. Takashima, M. Murayama, O. Murayama, T. Kohno, T. Honda, K. Yasutake, N.Nihonmatsu, M. Mercken, H. Yamaguchi, S. Sugihara, B. Wolozin, Presenilin1associates with glycogen synthase kinase-3and its substrate tau, Proc. Natl. Acad. Sci.USA95(1998)9637-9641.
53R. Gantier, D. Gilbert, C. Dumanchin, D. Campion, D. Davoust, F. Toma, T. Frebourg,The pathogenic L392V mutation of presenilin1decreases the affinity to glycogensynthase kinase-3, Neurosci. Lett.283(2000)217-220.
54C.A. Grimes, R.S. Jope, The multifaceted roles of glycogen synthase kinase3incellular signaling, Prog. Neurobiol.65(2001)391-426.
55R. Gómez-Sintes, F. Hernández, J.J. Lucas, J. Avila, Gsk-3mouse models to studyneuronal apoptosis and neurodegeneration, Front Mol. Neurosci.4(2011)45.
56J. Avila, F. Lim, F. Moreno, C. Belmonte,A.C. Cuello, Tau function and dysfunction inneurons: its role in neurodegenerative disorders, Mol. Neurobiol.25(2002)213-231.
57D. Terwel, R. Lasrado, J. Snauwaert, E. Vandeweert, C. Van Haesendonck, P.Borghgraef, F. Van Leuven, Changed conformation of mutant Tau-P301L underlies themoribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2Ntransgenic mice, J. Biol. Chem.280(2005):3963-3973.
1. Zhang P, Hinshaw JE.(2001) Three-dimensional reconstruction of dynamin in theconstricted state.Nat Cell Biol.3(10): p.922-926.
2. Smirnova E, et al.(2001) Dynaminrelated protein Drp1is required for mitochondrialdivision in mammalian cells. Mol Biol Cell.12:p.2245-2256.
3. Smirnova E, et al.(1998) A human dynamin-related protein controls the distribution ofmitochondria. J Cell Biol.143:p.351-358.
4. KR Pitts, et al.(1999) The Dynamin-like Protein DLP1Is Essential for NormalDistribution and Morphology of the Endoplasmic Reticulum and Mitochondria inMammalian Cells. Mol Biol Cell.10(12):p.4403–4417.
5. Glenn Marsboom, et al.(2012) Dynamin-Related Protein1–Mediated MitochondrialMitotic Fission Permits Hyperproliferation of Vascular Smooth Muscle Cells andOffers a Novel Therapeutic Target in Pulmonary Hypertension. Circulation Research.Circresaha.111:263848.
6. Taguchi N, et al.(2007) Mitotic phosphorylation of dynamin-related GTPaseDrp1participates in mitochondrial fission. J Biol Chem.282: p.11521–11529.
7. Cribbs JT, Strack S.(2007) Reversible phosphorylation of Drp1by cyclicAMP-dependent protein kinase and calcineurin regulates mitochondrial fission and celldeath. EMBO Rep.8: p.939–944.
8. Chang CR, Blackstone C.(2007) Cyclic AMP-dependent protein kinasephosphorylation of Drp1regulates its GTPase activity and mitochondrial morphology.J Biol Chem.282: p.21583–21587.
9. Xin Qi, et al.(2011) Aberrant mitochondrial fission in neurons induced by proteinkinase Cδ under oxidative stress conditions in vivo. Mol Biol Cell.22(2):256–265.
10. Kashatus DF, et al.(2011) RALA and RALBP1regulate mitochondrial fission atmitosis. Nat Cell Biol.13(9):p.1108-1115.
11. Liu JP, et al.(1996) Calcium binds dynamin I and inhibits its GTPase activity. JNeurochem.66(5): p.2074-2081.
12. Breckenridge DG, et al.(2003) Caspase cleavage product of BAP31inducesmitochondrial fission through endoplasmic reticulum calcium signals, enhancingcytochrome c release to the cytosol. J Cell Biol.160: p.1115-1127
13. Hom JR, et al.(2007) Thapsigargin induces biphasic fragmentation of mitochondriathrough calcium-mediated mitochondrial fission and apoptosis. J Cell Physiol.212(2):p.498-508.
14. Cereghetti GM, et al.(2008) Dephosphorylation by calcineurin regulates translocationof Drp1to mitochondria. Proc Natl Acad Sci U S A.105: p.15803–15808.
15. Han XJ, et al.(2008) CaM kinase I alpha-induced phosphorylation of Drp1regulatesmitochondrial morphology. J Cell Biol.182: p.573–585.
16. Wang W, et al.(2012) Mitochondrial fission triggered by hyperglycemia is mediated byROCK1activation in podocytes and endothelial cells. Cell Metabolism.15: p.186-200.
17.17． Cho DH, et al.(2009) S-nitrosylation of Drp1mediates beta-amyloid-relatedmitochondrial fission and neuronal injury. Science.324: p.102–105.
18. Harder Z, Zunino R, McBride H.(2004) Sumo1conjugates mitochondrial substratesand participates in mitochondrial fission. Curr Biol.14: p.340–345.
19. Claudia Figueroa-Romero, et al.(2009) SUMOylation of the mitochondrial fissionprotein Drp1occurs at multiple nonconsensus sites within the B domain and is linkedto its activity cycle. The FASEB Journal. p.11:3917-3927.
20. Liu QA, Shio H.(2008) Mitochondrial morphogenesis, dendrite development, andsynapse formation in cerebellum require both Bcl-w and the glutamate receptor delta2.PLoS Genet.6:e1000097.
21. Yoon Y, et al.(2003) The mitochondrial protein hFis1regulates mitochondrial fissionin mammalian cells through an interaction with the dynamin-like protein DLP1. MolCell Biol.15:p.5409-5420.
22. Stojanovski D, et al.(2004) Levels of human Fis1at the mitochondrial outer membraneregulate mitochondrial morphology. J Cell Sci.7:p.1201-1210.
23. Madhavika N，Serasinghe， Yisang Yoon.(2008) The mitochondrial outer membraneprotein hFis1regulates mitochondrial morphology and fission through self-interaction.Exp Cell Res.19: p.3494-3507.
24. Robert CW, et al.(2007) Direct Binding of the Dynamin-like GTPase, Dnm1,tomitochondrial Dynamics Protein Fis1is Negatively Regulated by the Fis1,N-terminalArm. J Biol Chem.46: p.33769-33775.
25. Lee YJ, et al.(2004) Roles of the mammalian mitochondrial fission and fusionmediators Fis1, Drp1, and Opa1in apoptosis. Mol Biol Cell.15: p.5001-5011.
26. Wasiak S, Zunino R, McBride HM.(2007) Bax/Bak promote sumoylation of DRP1and its stable association with mitochondria during apoptotic cell death. J Cell Biol.177: p.439-450.
27. Hidenori Otera, Chunxin Wang, Megan M.(2010) Mff is an essential factor formitochondrial recruitment of Drp1during mitochondrial fission in mammalian cells. JCell Biol.6: p.1141–1158.
28. Benard G, et al.(2007) Mitochondrial bioenergetics and structural networkorganization. J. Cell Sci.120: p.838-848
29. Philippe A. et al.(2008) Preventing Mitochondrial Fission Impairs MitochondrialFunction and Leads to Loss of Mitochondrial DNA. PLOS ONE. e3257: p.1-9
30. Adriana Malena, et al.(2009) Inhibition of Mitochondrial Fission Favours Mutant OverWild-type Mitochondrial DNA. Hum Mol Genet.18: p.3407-3416.
31. Gilad Twig, et al.(2008) Fission and selective fusion govern mitochondrial segregationand elimination by autophagy. EMBO J.27: p.433–446.
32. Seungmin Lee, et al.(2007) Mitochondrial Fission and Fusion Mediators, hFis1andOPA1,Modulate Cellular Senescence. J Biol Chem.282: p.22977–22983.
33. Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J.(2009) A hyperfusedmitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase.Proc NatlAcad Sci U SA.106(29): p.11960-11965.
34. Santel A, Fuller M.(2001) Control of mitochondrial morphology by a human mitofusin.J Cell Sci.114: p.867-874
35. Koshiba T, et al.(2004) Structural basis of mitochondrial tethering by mitofusincomplexes acting in trans. Science.305: p.858–862.
36. Ishihara N, Eura Y, and Mihara K.(2004) Mitofusin1and2play distinct roles inmitochondrial fusion reactions via GTPase activity. J Cell Sci.117: p.6535–6546.
37. Bourne HR, Sanders DA, McCormick F.(1991) The GTPase superfamily: conservedstructure and molecular mechanism. Nature.349(6305): p.117-127.
38. Chen H, et al.(2003) Mitofusins Mfn1and Mfn2coordinately regulate mitochondrialfusion and are essential for embryonic development. J Cell Biol.160(2): p.189-200.
39. de Brito OM, Scorrano L.(2008) Mitofusin2tethers endoplasmic reticulum tomitochondria. Nature.456(7222): p.605-610
40. Rojo M, Legros F, Chateau D, Lomebs A.(2002) Membrane topology andmitochondrial targeting of mitofusins, ubiquitous mammalian homologues of thetransmembrane GTPase Fzo. J Cell Sci.115: p.1663-1674.
41. Delettre C, et al.(2001) Mutation spectrum and splicing variants in the OPA1gene.Hum Genet,109: p.584–591.
42. Satoh M, Hamamoto T, Seo N, Kagawa Y. and Endo H.(2003) Differentialsublocalization of the dynamin-related protein OPA1isoforms in mitochondria.Biochem Biophy Res Commun.300: p.482–493.
43. Frezza C, et al.(2006) OPA1controls apoptototic cristae remoding independently frommitochondrial fusion. Cell.126: p.177-189.
44. Meeusen S, et al.(2006) Mitochondrial inner-membrane fusion and crista maintenancerequires the dynamin-related GTPase Mgm1. Cell.127(2): p.383-395.
45. Sesaki H, Jensen RE.(2004) Ugo1p links the Fzo1p and Mgm1p GTPases formitochondrial fusion. J Biol Chem.279(27): p.28298-28303.
46. Shelly Meeusen J，et al.(2004) Mitochondrial Fusion Intermediates Revealed in Vitro.Science.17: p.1747-1752.
47. Legros F, Lombes A,43. Frachon P, Rojo M.(2002) Mitochondrial fusion in humancell is efficient, requires inner membrane potential and Mitofusin. Mol Biol Cell.13: p.4343-4354.
48. Malka F, et al.(2005) Separate fusion of outer and inner mitochondrial membranes.EMBO Rep.6(9): p.853-859.
49. Zhiyin Song, et al.(2009) Mitofusins and OPA1Mediate Sequential Steps inMitochondrial Membrane Fusion. Mol Biol Cell.20(15): p.3525-3532.
50. Cohen MM, et al.(2008) Ubiquitin-Proteasmome-dependent degradation of amitofusion, a critical regulator of mitochondrial fusion. Mol Biol Cell.19: p.2454-2464.
51. Noriyuki Matsuda, et al.(2010) PINK1stabilized by mitochondrial depolarizationrecruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. JCell Biol.189: p.211-221.
52. Matthew EG, J Mark Cooper (2010) Mitofusin1and Mitofusin2are ubiquitinated in aPINK1parkin dependent manner upon mitophagy. Hum Mol Genet.19(24): p.4861-4870.
53. Guillery O, et al.(2008) Metalloprotease-mediated OPA1processing is modulated bythe mitochondrial membrane potential. M Biol Cell.100(5): p.315-325.
54. McQuibban GA, Saurya S, Freeman M.(2003) Mitochondrial membrane remodellingregulated by a conserved rhomboid protease. Nature.423(6939): p.537-541.
55. Ehses S, Raschke I, Mancuso G,(2009) Regulation of OPA1processing andmitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol.187(7):p.1023-1036.
56. Hsiuchen Chen, et al.(2010) Mitochondrial Fusion Is Required for mtDNA Stability inSkeletal Muscle and Tolerance of mtDNA Mutations. Cell.141: p.280–289.
57. Daniel Tondera, et al.(2009) SLP-2is required for stress-induced mitochondrialhyperfusion. The EMBO Journal.28: p.1589–1600.
58. Angelika S. Rambold, Brenda Kostelecky, Natalie Elia, and JenniferLippincott-Schwartz.(2011).Tubular network formation protects mitochondria fromautophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A.108(25): p.10190-10195.
59. Mariusz Karbowski, Seon-Yong Jeong, Richard J. Youle.(2004) Endophilin B1isrequired for the maintenance of mitochondrial morphology. J Cell Biol.166(7): p.1027-1039.
60. Arnoult D, et al.(2005) Bax/Bak-dependent release of DDP/TIMM8a promotesDrp1-mediated mitochondrial fission and mitoptosis during programmed cell death.Curr Biol.15(23): p.2112-2118.
61. Niemann A, Ruegg M, La Padula V, Schenone A, Suter U.(2005) Ganglioside-induceddifferentiation associated protein1is a regulator of the mitochondrial network: newimplications for Charcot-Marie-Tooth disease. J Cell Biol.170(7): p.1067-1078.
62. Wagner KM, Rüegg M, Niemann A, Suter U.(2009) Targeting and function of themitochondrial fission factor GDAP1are dependent on its tail-anchor. PLoS One.4(4):e5160.
63. Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S.(2006) MARCH-V is a novelmitofusin2-and Drp1-binding protein able to change mitochondrial morphology.EMBO Rep.7(10): p.1019-1022.
64. Karbowski M, Neutzner A, Youle RJ.(2007) The mitochondrial E3ubiquitin ligaseMARCH5is required for Drp1dependent mitochondrial division. J Cell Biol.178(1): p.71-84.
65. Park YY, Lee S, Karbowski M, Neutzner A, Youle RJ, Cho H.(2010) Loss ofMARCH5mitochondrial E3ubiquitin ligase induces cellular senescence throughdynamin-related protein1and mitofusin1. J Cell Sci.123(Pt4): p.619-626.
66. Gandre-Babbe S and AM van der Bliek (2008) The novel tail-anchored membraneprotein Mff controls mitochondrial and peroxisomal fission in mammalian cells. MolBiol Cell.19(6): p.2402-2412.
67. Parcellier A, et al.(2009) The Carboxy-Terminal Modulator Protein (CTMP) regulatesmitochondrial dynamics. PLoS One.4(5): p. e5471.
68. Aihara T, et al.(2009) A novel potential role for gametogenetin-binding protein1(GGNBP1) in mitochondrial morphogenesis during spermatogenesis in mice. BiolReprod.80(4): p.762-770.
69. Choi SY, et al.(2006) A common lipid links Mfn-mediated mitochondrial fusion andSNARE-regulated exocytosis. Nat Cell Biol.8(11): p.1255-1262.
70. Huang, H. and M.A. Frohman,(2009) Lipid signaling on the mitochondrial surface.Biochim Biophys Acta.1791(9): p.839-844.
71. Li J, et al.(2012) Lysocardiolipin acyltransferase1(ALCAT1) controls mitochondrialDNA fidelity and biogenesis through modulation of MFN2expression. Proc Natl AcadSci U S A. May1;109(18):6975-6980. Epub2012Apr16.
72. Eura Y, et al.(2006) Identification of a novel protein that regulates mitochondrialfusion by modulating mitofusin (Mfn) protein function. J Cell Sci.119(Pt23): p.4913-4925.
73. Zhao J, et al.(2011) Human MIEF1recruits Drp1to mitochondrial outer membranesand promotes mitochondrial fusion rather than fission. EMBO J.30(14): p.2762-2778.
74. Liesa M, et al.(2008) Mitochondrial fusion is increased by the nuclear coactivatorPGC-1beta. PLoS One.3(10): p. e3613.
75. Wang K, et al.(2012) miR-484regulates mitochondrial network through targeting Fis1.Nat Commun.3: p.781.
76. Frank S, et al.(2001) The role of dynamin-related protein1, a mediator ofmitochondrial fission, in apoptosis. Dev Cell.1(4): p.515-525.
77. James DI, et al.(2003) hFis1, a novel component of the mammalian mitochondrialfission machinery. J Biol Chem.278(38): p.36373-36379.
78. Sugioka R, S Shimizu and Y Tsujimoto.(2004) nFzo1, a protein involved inmitochondrial fusion, inhibits apoptosis. J Biol Chem.279(50): p.52726-52734.
79. Olichon A, et al.(2003) Loss of OPA1perturbates the mitochondrial inner membranestructure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem.278(10): p.7743-7746.
80. Karbowski M, et al.(2002) Spatial and temporal association of Bax with mitochondrialfission sites, Drp1, and Mfn2during apoptosis. J Cell Biol.159(6): p.931-938.
81. Neuspiel M, et al.(2005) Activated mitofusin2signals mitochondrial fusion, interfereswith Bax activation, and reduces susceptibility to radical induced depolarization. J BiolChem.280(26): p.25060-25070.
82. Sheridan C, et al.(2008) Bax-or Bak-induced mitochondrial fission can be uncoupledfrom cytochrome C release. Mol Cell.31(4): p.570-585.
83. Hom JR, et al.(2007) Thapsigargin induces biphasic fragmentation of mitochondriathrough calcium-mediated mitochondrial fission and apoptosis. J Cell Physiol.212(2):p.498-508.
84. Alirol E, et al.(2006) The mitochondrial fission protein hFis1requires the endoplasmicreticulum gateway to induce apoptosis. Mol Biol Cell.17(11): p.4593-4605.
85. Parone PA, et al.,(2006) Inhibiting the mitochondrial fission machinery does notprevent Bax/Bak-dependent apoptosis. Mol Cell Biol.26(20): p.7397-7408.
86. Chen H, et al.(2003) Mitofusins Mfn1and Mfn2coordinately regulate mitochondrialfusion and are essential for embryonic development. J Cell Biol.160(2): p.189-200.
87. Chen H, A Chomyn and DC Chan,(2005) Disruption of fusion results in mitochondrialheterogeneity and dysfunction. J Biol Chem.280(28): p.26185-26192.
88. Hirai K, et al.(2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci.21(9): p.3017-3023.
89. Wang X, et al.(2008) Dynamin-like protein1reduction underlies mitochondrialmorphology and distribution abnormalities in fibroblasts from sporadic Alzheimer'sdisease patients. Am J Pathol.173(2): p.470-482.
90. Wang X, et al.(2009) Impaired balance of mitochondrial fission and fusion inAlzheimer's disease. J Neurosci.29(28): p.9090-9103.
91. Manczak M, MJ Calkins and PH Reddy (2011) Impaired mitochondrial dynamics andabnormal interaction of amyloid beta with mitochondrial protein Drp1in neurons frompatients with Alzheimer's disease: implications for neuronal damage. Hum Mol Genet.20(13): p.2495-2509.
92. Tatebayashi Y, et al.(2004) Role of tau phosphorylation by glycogen synthasekinase-3beta in the regulation of organelle transport. J Cell Sci.117(Pt9): p.1653-1663.
93. Shahpasand K, et al.(2012) Regulation of mitochondrial transport andinter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated inAlzheimer's disease. J Neurosci.32(7):2430-2441.
94. Kanaan NM, et al.(2012) Phosphorylation in the amino terminus of tau preventsinhibition of anterograde axonal transport. Neurobiol Aging.33(4): p.826.e15-30
95. Quintanilla RA, et al.(2009) Caspase-cleaved tau expression induces mitochondrialdysfunction in immortalized cortical neurons: implications for the pathogenesis ofAlzheimer disease. J Biol Chem.284(28): p.18754-18766.
96. Amadoro G, et al.(2010) A NH2tau fragment targets neuronal mitochondria at ADsynapses: possible I implications for neurodegeneration. J Alzheimers Dis.21(2): p.445-470.
97. Rhein V, et al.(2009) Amyloid-beta and tau synergistically impair the oxidativephosphorylation system in triple transgenic Alzheimer's disease mice. Proc Natl AcadSci U S A.106(47): p.20057-20062.
98. Kopeikina KJ, et al.(2011) Tau accumulation causes mitochondrial distributiondeficits in neurons in a mouse model of tauopathy and in human Alzheimer's diseasebrain. Am J Pathol.179(4): p.2071-2082.
99. Manczak M, Reddy PH.(2012) Abnormal interaction between the mitochondrialfission protein Drp1and hyperphosphorylated tau in Alzheimer's disease neurons:implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet.Mar13.[Epub ahead of print].
100.Manczak M, Sesaki H, Kageyama Y, Reddy PH.(2012) Dynamin-related protein1heterozygote knockout mice do not have synaptic and mitochondrial deficiencies.Biochim BiophysActa.1822(6):862-874. Epub2012Feb23.
101.A Atlante, et al.(2008) A peptide containing residues26–44of tau protein impairsmitochondrial oxidative phosphorylation acting at the level of the adenine nucleotidetranslocator. Biochim BiophysActa.1777(10):1289-300.
102.Cristian ALR, et al.(2011) Tau oligomers impair memory and induce synaptic andmitochondrial dysfunction in wild-type mice. Mol Neurodegeneration.6:39.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |