Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice

详细信息    查看全文

• 作者：Linghua Qiu (1)
  Tao Qiao (1)
  Melissa Beers (1) (2)
  Weijia Tan (1)
  Hongyan Wang (1)
  Bin Yang (1) (3)
  Zuoshang Xu (1) (4) (5)
  
• 关键词：VAPB ; ALS ; Motor neuron disease ; Neurodegeneration ; Transgenic mice
• 刊名：Molecular Neurodegeneration
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：8
• 期：1
• 全文大小：1738KB
• 参考文献：1. Figlewicz DA, Orrell RW: The genetics of motor neuron diseases. / Amyotroph Lateral Scler Other Motor Neuron Disord 2003, 4:225鈥?31. CrossRef
  2. Andersen PM, Al-Chalabi A: Clinical genetics of amyotrophic lateral sclerosis: what do we really know? / Nat Rev Neurol 2011, 7:603鈥?15. CrossRef
  3. Marques VD, Barreira AA, Davis MB, Abou-Sleiman PM, Silva WA Jr, Zago MA, Sobreira C, Fazan V, Marques W Jr: Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. / Muscle Nerve 2006, 34:731鈥?39. CrossRef
  4. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, / et al.: A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. / Am J Hum Genet 2004, 75:822鈥?31. CrossRef
  5. Chen HJ, Anagnostou G, Chai A, Withers J, Morris A, Adhikaree J, Pennetta G, de Belleroche JS: Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. / J Biol Chem 2010, 285:40266鈥?0281. CrossRef
  6. De Vos KJ, Morotz GM, Stoica R, Tudor EL, Lau KF, Ackerley S, Warley A, Shaw CE, Miller CC: VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. / Hum Mol Genet 2012, 21:1299鈥?311. CrossRef
  7. Fasana E, Fossati M, Ruggiano A, Brambillasca S, Hoogenraad CC, Navone F, Francolini M, Borgese N: A VAPB mutant linked to amyotrophic lateral sclerosis generates a novel form of organized smooth endoplasmic reticulum. / FASEB J 2010, 24:1419鈥?430. CrossRef
  8. Kagiwada S, Hosaka K, Murata M, Nikawa J, Takatsuki A: The Saccharomyces cerevisiae SCS2 gene product, a homolog of a synaptobrevin-associated protein, is an integral membrane protein of the endoplasmic reticulum and is required for inositol metabolism. / J Bacteriol 1998, 180:1700鈥?708.
  9. Kaiser SE, Brickner JH, Reilein AR, Fenn TD, Walter P, Brunger AT: Structural basis of FFAT motif-mediated ER targeting. / Structure 2005, 13:1035鈥?045. CrossRef
  10. Kanekura K, Nishimoto I, Aiso S, Matsuoka M: Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). / J Biol Chem 2006, 281:30223鈥?0233. CrossRef
  11. Skehel PA, Fabian-Fine R, Kandel ER: Mouse VAP33 is associated with the endoplasmic reticulum and microtubules. / Proc Natl Acad Sci U S A 2000, 97:1101鈥?106. CrossRef
  12. Teuling E, Ahmed S, Haasdijk E, Demmers J, Steinmetz MO, Akhmanova A, Jaarsma D, Hoogenraad CC: Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. / J Neurosci 2007, 27:9801鈥?815. CrossRef
  13. Skehel PA, Martin KC, Kandel ER, Bartsch D: A VAMP-binding protein from Aplysia required for neurotransmitter release. / Science 1995, 269:1580鈥?583. CrossRef
  14. Amarilio R, Ramachandran S, Sabanay H, Lev S: Differential regulation of endoplasmic reticulum structure through VAP-Nir protein interaction. / J Biol Chem 2005, 280:5934鈥?944. CrossRef
  15. Soussan L, Burakov D, Daniels MP, Toister-Achituv M, Porat A, Yarden Y, Elazar Z: ERG30, a VAP-33-related protein, functions in protein transport mediated by COPI vesicles. / J Cell Biol 1999, 146:301鈥?11. CrossRef
  16. Pennetta G, Hiesinger PR, Fabian-Fine R, Meinertzhagen IA, Bellen HJ: Drosophila VAP-33A directs bouton formation at neuromuscular junctions in a dosage-dependent manner. / Neuron 2002, 35:291鈥?06. CrossRef
  17. Morotz GM, De Vos KJ, Vagnoni A, Ackerley S, Shaw CE, Miller CC: Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria. / Hum Mol Genet 2012, 21:1979鈥?988. CrossRef
  18. Tsuda H, Han SM, Yang Y, Tong C, Lin YQ, Mohan K, Haueter C, Zoghbi A, Harati Y, Kwan J, / et al.: The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. / Cell 2008, 133:963鈥?77. CrossRef
  19. Han SM, Tsuda H, Yang Y, Vibbert J, Cottee P, Lee SJ, Winek J, Haueter C, Bellen HJ, Miller MA: Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors. / Dev Cell 2012, 22:348鈥?62. CrossRef
  20. Gkogkas C, Middleton S, Kremer AM, Wardrope C, Hannah M, Gillingwater TH, Skehel P: VAPB interacts with and modulates the activity of ATF6. / Hum Mol Genet 2008, 17:1517鈥?526. CrossRef
  21. Langou K, Moumen A, Pellegrino C, Aebischer J, Medina I, Aebischer P, Raoul C: AAV-mediated expression of wild-type and ALS-linked mutant VAPB selectively triggers death of motoneurons through a Ca2 + 鈭抎ependent ER-associated pathway. / J Neurochem 2010, 114:795鈥?09. CrossRef
  22. Suzuki H, Kanekura K, Levine TP, Kohno K, Olkkonen VM, Aiso S, Matsuoka M: ALS-linked P56S-VAPB, an aggregated loss-of-function mutant of VAPB, predisposes motor neurons to ER stress-related death by inducing aggregation of co-expressed wild-type VAPB. / J Neurochem 2009, 108:973鈥?85. CrossRef
  23. Kim S, Leal SS, Ben Halevy D, Gomes CM, Lev S: Structural requirements for VAP-B oligomerization and their implication in amyotrophic lateral sclerosis-associated VAP-B(P56S) neurotoxicity. / J Biol Chem 2010, 285:13839鈥?3849. CrossRef
  24. Tudor EL, Galtrey CM, Perkinton MS, Lau KF, De Vos KJ, Mitchell JC, Ackerley S, Hortobagyi T, Vamos E, Leigh PN, / et al.: Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology. / Neuroscience 2010, 167:774鈥?85. CrossRef
  25. Ratnaparkhi A, Lawless GM, Schweizer FE, Golshani P, Jackson GR: A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. / PLoS One 2008, 3:e2334. CrossRef
  26. Anagnostou G, Akbar MT, Paul P, Angelinetta C, Steiner TJ, de Belleroche J: Vesicle associated membrane protein B (VAPB) is decreased in ALS spinal cord. / Neurobiol Aging 2011, 31:969鈥?85. CrossRef
  27. Chai A, Withers J, Koh YH, Parry K, Bao H, Zhang B, Budnik V, Pennetta G: hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction. / Hum Mol Genet 2008, 17:266鈥?80. CrossRef
  28. Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW: Onset and progression in inherited ALS determined by motor neurons and microglia. / Science 2006, 312:1389鈥?392. CrossRef
  29. Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW: Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. / Nat Neurosci 2008, 11:251鈥?53. CrossRef
  30. Qiu L, Rivera-Perez JA, Xu Z: A Non-specific effect associated with conditional transgene expression based on Cre-loxP strategy in mice. / PLoS One 2011, 6:e18778. CrossRef
  31. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, / et al.: Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. / Neuron 2011, 72:245鈥?56. CrossRef
  32. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T: TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. / Biochem Biophys Res Commun 2006, 351:602鈥?11. CrossRef
  33. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, / et al.: Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. / Science 2006, 314:130鈥?33. CrossRef
  34. Mackenzie IR, Rademakers R, Neumann M: TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. / Lancet Neurol 2010, 9:995鈥?007. CrossRef
  35. Balch WE, Morimoto RI, Dillin A, Kelly JW: Adapting proteostasis for disease intervention. / Science 2008, 319:916鈥?19. CrossRef
  36. Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI: Progressive disruption of cellular protein folding in models of polyglutamine diseases. / Science 2006, 311:1471鈥?474. CrossRef
  37. Bergemalm D, Forsberg K, Srivastava V, Graffmo KS, Andersen PM, Brannstrom T, Wingsle G, Marklund SL: Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice. / J Neurochem 2010, 114:408鈥?18. CrossRef
  38. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW: ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. / Neuron 1997, 18:327鈥?38. CrossRef
  39. Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, 3rd White CL, Bigio EH, Caselli R, / et al.: TDP-43 A315T mutation in familial motor neuron disease. / Ann Neurol 2008, 63:535鈥?38. CrossRef
  40. Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, / et al.: TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. / Nat Genet 2008, 40:572鈥?74. CrossRef
  41. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, / et al.: TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. / Science 2008, 319:1668鈥?672. CrossRef
  42. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, / et al.: Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. / Science 2009, 323:1208鈥?211. CrossRef
  43. Barmada SJ, Skibinski G, Korb E, Rao EJ, Wu JY, Finkbeiner S: Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. / J Neurosci 2010, 30:639鈥?49. CrossRef
  44. Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH: TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. / Proc Natl Acad Sci U S A 2009, 106:18809鈥?8814. CrossRef
  45. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S: Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. / Nature 2004, 431:805鈥?10. CrossRef
  46. Xu Z: Does a loss of TDP-43 function cause neurodegeneration? / Mol Neurodegener 2012, 7:27. CrossRef
  47. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, / et al.: Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. / Cell 2010, 141:1146鈥?158. CrossRef
  48. Mitne-Neto M, Machado-Costa M, Marchetto MC, Bengtson MH, Joazeiro CA, Tsuda H, Bellen HJ, Silva HC, Oliveira AS, Lazar M, / et al.: Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. / Hum Mol Genet 2010, 20:3642鈥?652. CrossRef
  49. Qiu L, Wang H, Xia X, Zhou H, Xu Z: A construct with fluorescent indicators for conditional expression of miRNA. / BMC Biotechnol 2008, 8:77. CrossRef
  50. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, / et al.: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. / Science 1994, 264:1772鈥?775. CrossRef
  
• 作者单位：Linghua Qiu (1)
  Tao Qiao (1)
  Melissa Beers (1) (2)
  Weijia Tan (1)
  Hongyan Wang (1)
  Bin Yang (1) (3)
  Zuoshang Xu (1) (4) (5)
  
  1. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, 01602, USA
  2. Department of Biological Sciences, Wellesley College, Wellesley, MA, 02481, USA
  3. Division of Biology, California Institute of Technology, Pasadena, CA, 91125, USA
  4. Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, 01602, USA
  5. Neuroscience Program, University of Massachusetts Medical School, Worcester, MA, 01602, USA
  

文摘

Background A proline-to-serine substitution at position-56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) causes a form of dominantly inherited motor neuron disease (MND), including typical and atypical amyotrophic lateral sclerosis (ALS) and a mild late-onset spinal muscular atrophy (SMA). VAPB is an integral endoplasmic reticulum (ER) protein and has been implicated in various cellular processes, including ER stress, the unfolded protein response (UPR) and Ca2+ homeostasis. However, it is unclear how the P56S mutation leads to neurodegeneration and muscle atrophy in patients. The formation of abnormal VAPB-positive inclusions by mutant VAPB suggests a possible toxic gain of function as an underlying mechanism. Furthermore, the amount of VAPB protein is reported to be reduced in sporadic ALS patients and mutant SOD1G93A mice, leading to the hypothesis that wild type VAPB plays a role in the pathogenesis of ALS without VAPB mutations. Results To investigate the pathogenic mechanism in vivo, we generated human wild type (wtVAPB) and mutant VAPB (muVAPB) transgenic mice that expressed the transgenes broadly in the CNS. We observed robust VAPB-positive aggregates in the spinal cord of muVAPB transgenic mice. However, we failed to find an impairment of motor function and motor neuron degeneration. We also did not detect any change in the endogenous VAPB level or evidence for induction of the unfolded protein response (UPR) and coaggregation of VAPA with muVAPB. Furthermore, we crossed these VAPB transgenic mice with mice that express mutant SOD1G93A and develop motor neuron degeneration. Overexpression of neither wtVAPB nor muVAPB modulated the protein aggregation and disease progression in the SOD1G93A mice. Conclusion Overexpression of VAPBP56S mutant to approximately two-fold of the endogenous VAPB in mouse spinal cord produced abundant VAPB aggregates but was not sufficient to cause motor dysfunction or motor neuron degeneration. Furthermore, overexpression of either muVAPB or wtVAPB does not modulate the course of ALS in SOD1G93A mice. These results suggest that changes in wild type VAPB do not play a significant role in ALS cases that are not caused by VAPB mutations. Furthermore, these results suggest that muVAPB aggregates are innocuous and do not cause motor neuron degeneration by a gain-of-toxicity, and therefore, a loss of function may be the underlying mechanism.