Aβ对c-Fos和SUMO-1在海马表达的影响
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摘要
阿尔茨海默病(Alzheimer disease, AD)是以智能衰退为主要表现的神经系统退行性疾病。AD的主要病理特征为脑内分布有由大量的β-淀粉样蛋白(β-amyloid, Aβ)沉积形成的老年斑(senile plaque, SP)、神经元内高度磷酸化tau蛋白聚集形成的神经原纤维缠结(neurofibrillary tangle)、神经元营养障碍、神经元的大量丢失、突触的损害和丢失。目前AD的病因尚不清楚,但Aβ神经毒性被认为是各种因素引起AD的共同通路。本实验分别在AD转基因鼠和在脑内注入Aβ的SD大鼠动物模型上探讨Aβ对c-Fos和小泛素相关修饰物(small ubiquitin-related modifer, sumo-1)在海马内表达的影响。主要研究结果如下：
第一部分：Aβ诱导c-Fos的表达：
1.免疫组织化学检测显示12月龄APPswe/PS1ΔE9 AD转基因鼠脑内有大量的β-淀粉样蛋白沉积形成的斑块。同12月龄野生型小鼠相比,Fos蛋白表达显著增加,Fos免疫阳性染色主要分布在海马CA1-4区的锥体细胞层、齿状回、丘脑、下丘脑等部位的神经元胞核内。
2.SD大鼠背海马内注入不同剂量的Aβ1-40,免疫组化检测显示：在3小时2nmol组Fos蛋白被诱导表达最多,Fos阳性的神经元主要分布在海马CA3／4区的锥体细胞层、齿状回门区内和颗粒细胞层,以CA3／4区和门区内最为明显。0.02nmol和0.2nmol组在海马齿状回门区内以及颗粒细胞下层可见散在的Fos阳性细胞核染色。2nmol组Aβ1-40注射6小时后的Fos蛋白表达同生理盐水对照组无明显差异。
3.SD大鼠海马内分别注射2nmol的Aβ1-28和Aβ25-35后3小时,免疫组织化学结果显示海马齿状回的颗粒细胞层下部及其门区内,以及CA3区的锥体细胞层可见Fos表达增加,但不如注入2nmol Aβ1-40组明显。Aβ25-35诱导Fos表达的效应较Aβ1-28强。
4.SD大鼠侧脑室内分别注射0.02、0.2、2nmol Aβ1-40后3小时,也可见在齿状回门区内和颗粒细胞层下部以及CA3区Fos阳性染色。注射海人藻酸(Kainic Acid,KA)3小时诱导的Fos高表达,主要分布于CA区锥体细胞层和齿状回颗粒细胞层的神经元,其中CA3区表达相对较弱,6小时后Fos表达减弱。而同时注射Aβ或用γ-分泌酶抑制剂阻止Aβ形成,可影响KA诱导的Fos在海马表达的分布模式。
5. SD大鼠海马内注入2nmol的Aβ1-40后观察到海马内神肽Y(neuropeptide Y, NPY)的分布减少。免疫荧光双标Fos与NPY的结果显示：Fos与NPY的有部分共存,但Aβ1-40作用后Fos染色增加,NPY染色减弱,Fos与NPY的共存细胞减少。
第二部分：Aβ对脑内SUMO-1表达和分布的影响：
1.免疫组织化学和Western-blot检测显示：12月龄APPswe／PS1ΔE9 AD转基因鼠脑内SUMO-1表达较同月龄的野生型小鼠增加；转基因鼠海马SUMO-1阳性染色的部位主要为神经纤维分布的部位,包括苔状纤维,齿状回的颗粒细胞层外的分子层,而颗粒细胞层和锥体细胞层的胞体部位染色浅；皮层沉积老年斑内也可见SUMO-1的免疫阳性染色。12月龄野生型鼠SUMO-1在锥体细胞层淡染,颗粒细胞层较周围分布有神经纤维的部分染色更浅。
2.SD大鼠海马内注射Aβ,在不同的时间点应用ABC法检测SUMO-1表达和分布。结果显示：注入单体可溶性Aβ1-40后,SUMO-1在海马CA区锥体细胞层的表达随着时间的延长逐渐增加,在7天时表达最多；在注射纤维状Aβ1-40后注射部位附近的CA1区神经元有SUMO-1阳性染色,在7天时可以观察到在注射部位周围类似瘢痕组织的结构附近有较多的SUMO-1阳性纤维。同时也观察到在注射后的不同时间点皮层内有散在的团块状SUMO-1阳性染色。
3.昆明鼠的冷水应激后观察到Aβ免疫荧光染色增强。免疫组化和Western-blot技术检测显示,在应激12小时后脑内SUMO-1表达显著增加。正常动物SUMO-1主要分布在海马锥体细胞和齿状回内颗粒细胞的胞体,但染色较淡；在应激后海马脑片SUMO-1染色显著加深,免疫阳性物质主要分布在海马齿状回分子层、苔状纤维以及CA区放射层的区域。
综上所述,AD转基因动物海马内有c-fos和SUMO-1表达增加；不同浓度和肽段的Aβ短时间内可以诱导海马Fos表达增加并显示不同的分布模式,Aβ还可诱导NPY表达减少；Aβ可长时程诱导SUMO-1表达的改变。应激后脑内的有Aβ生成增加和SUMO-1表达增加,SUMO-1分布模式类似AD转基因动物。
The characteristic pathological changes of Alzheimer's disease (AD) include extracellular senile plaques formed by accumulated P-amyloid proteins(Aβ), the neurofibrillar tangles formed by abnormal phosphorylated tau, neuronal dystrophy and neuronal loss, neurotransmitter system impairment and so on. The exact etiological factor of AD is still unclear,but the neuronal toxicity of Aβis considered to identical factor in process of AD onset.In this experiment, we did some researches on exploring the possible effects of Aβon the expression of immediate early gene product c-Fos and posttranslational modifier small ubiquitin related-modifier (sumo-1). The main research results are as follows:
Part I
1.Using immunohistochemical staining, we found that there was a lot of senile plaques formed by accumulatedβ-amyloid proteins in the brain of 12 months transgenic mice with human APPswe and PS1 mutant (APPswe/PS1ΔAE9).The expression of Fos was increased with wildtype control and the Fos mainly distributed in cell body including pyramidal cell layer(PL) of hippocampus thalamus, hypothalamus and so on.
2.We injected different dose of soluble and fresh Aβ1-40 (2nmol,0.2nmol, 0.02nmol) into hippocampus. After three hours, the dose of 2nmol Aβ1-40 could induce the Fos expression in PL of hippocampus CA3/4, hilus and granular cells layer(GL) of gyrus dentate(DG),particularly in PL and hilus. In the dose of 0.2nml and 0.02nmol, we observed sporadic Fos immunopositive cells in hilus and GL near cerebral ventricle of DG. After six hours or longer time, the c-fos expression in hippocampus did not significantly change with control.
3. we injected Aβ1-28 and Aβ25-35. into hippocampus at dose of 2nmol.Three hours later, immunohistochemistry staing results showed that Fos immunopositive staining was increased in hilus and GL of DG near cerebral ventricle and PL of hippocampus CA3 but not obvious like Aβ1-40 group.The effects of Aβ25-35 on inducing Fos expression was more powerful than Aβ1-28.
4. We intracerebralventricularly injected Aβ1-40(0.02 nmol,0.2 nmol,2nmol). Three hours later,Fos positive staining chiefly distributed in the hilus and GL of DG and PL of hippocampus CA3. On brain slice of intracerebralventricular injection KA(1μg) three hours, Fos also were highly induced in the neuron of PL of hippocampus and GL of dentate gyrus. After six hours, the expression of Fos was decreased. we injected KA and Aβon the same time or KA and inhibitor of y-secreates that inhibited Aβgeneration, Fos expression and distribution was different from that was induced by KA.
5. We found that the NPY expression in the DG of rats that was injected 2nmol Aβ1-40 into hippocampus was lower than normal animal. We performed immuno-fluorescence double labeling and observed that Fos was partly colocalized with NPY. NPY expression was decreased accompanied by Fos enhanced, so there was less neuron that Fos colocalized with NPY.
PartⅡ
1. Immunohistochemical and immunoblot analysis revealed that the SUMO-1 expression of 12 months APPswe/PS1ΔE9 transgenic mice was increased with widetype control. The SUMO-1 positive staining were mainly localized in nerve fiber including mossy fiber and molecular layer out of GL of DG,but the staining of the PL and GL cell body was bland.Alternatively, there were SUMO-1 immunopositive senile plaque in cortex.In widetype mice, the SUMO-1 expression was lower in the PL and GL than the transgenic mouse. These showed that SUMO-1 may be related to AD.
2. We employed the Sprague-Dawley rats model that were injected different aggregation Aβ1-40 (soluble and fresh Aβ1-40 or fibril Aβ1-40) into hippocampus. After different injection time (1day,3days and 7days), using immunohistochemical staining we observered the Fos expression. In soluble and fresh group,the SUMO-1 positive cells were increased in the PL of hippocampus CA2/3 and were most on 7 days. In fibril group, there were SUMO-1 immunopositive neurons nearly injection region of hippocampus CA1 on the first day. On the seventh day, a lot of SUMO-1 immunopositive fiber distributed in the injection site. Interestingly, in the cortex and injection region,we also seen a little of clustered SIG on different time.
3. we confirmed that in the brain of cold stress mouse the expression of the Aβwas increased. the analyses immunohistochemical and immunoblot showed that SUMO-1 was bland staining in the body of PL of hippocampus CA1-3 region and GL of DG in normal animals. After cold stress the staining of SUMO-1 was increased in whole hippocampus and mainly distributed in molecular layer of DG, mossy fiber and stratum radiatum layer
In a word, Fos and SUMO-1 expression on the hippocampus of transgenic mouse was increased with widetype. Different dose and peptides Aβcould induce the expression and distribution change of Fos in a short time.Aβalso could induce SUMO-1 expression changed in long time. After cold stress, Aβand SUMO-1 expression was increased and the distribution of SUMO-1 was similar with the transgenic mouse.
第一部分：Aβ诱导c-Fos的表达：
1.免疫组织化学检测显示12月龄APPswe/PS1ΔE9 AD转基因鼠脑内有大量的β-淀粉样蛋白沉积形成的斑块。同12月龄野生型小鼠相比,Fos蛋白表达显著增加,Fos免疫阳性染色主要分布在海马CA1-4区的锥体细胞层、齿状回、丘脑、下丘脑等部位的神经元胞核内。
2.SD大鼠背海马内注入不同剂量的Aβ1-40,免疫组化检测显示：在3小时2nmol组Fos蛋白被诱导表达最多,Fos阳性的神经元主要分布在海马CA3／4区的锥体细胞层、齿状回门区内和颗粒细胞层,以CA3／4区和门区内最为明显。0.02nmol和0.2nmol组在海马齿状回门区内以及颗粒细胞下层可见散在的Fos阳性细胞核染色。2nmol组Aβ1-40注射6小时后的Fos蛋白表达同生理盐水对照组无明显差异。
3.SD大鼠海马内分别注射2nmol的Aβ1-28和Aβ25-35后3小时,免疫组织化学结果显示海马齿状回的颗粒细胞层下部及其门区内,以及CA3区的锥体细胞层可见Fos表达增加,但不如注入2nmol Aβ1-40组明显。Aβ25-35诱导Fos表达的效应较Aβ1-28强。
4.SD大鼠侧脑室内分别注射0.02、0.2、2nmol Aβ1-40后3小时,也可见在齿状回门区内和颗粒细胞层下部以及CA3区Fos阳性染色。注射海人藻酸(Kainic Acid,KA)3小时诱导的Fos高表达,主要分布于CA区锥体细胞层和齿状回颗粒细胞层的神经元,其中CA3区表达相对较弱,6小时后Fos表达减弱。而同时注射Aβ或用γ-分泌酶抑制剂阻止Aβ形成,可影响KA诱导的Fos在海马表达的分布模式。
5. SD大鼠海马内注入2nmol的Aβ1-40后观察到海马内神肽Y(neuropeptide Y, NPY)的分布减少。免疫荧光双标Fos与NPY的结果显示：Fos与NPY的有部分共存,但Aβ1-40作用后Fos染色增加,NPY染色减弱,Fos与NPY的共存细胞减少。
第二部分：Aβ对脑内SUMO-1表达和分布的影响：
1.免疫组织化学和Western-blot检测显示：12月龄APPswe／PS1ΔE9 AD转基因鼠脑内SUMO-1表达较同月龄的野生型小鼠增加；转基因鼠海马SUMO-1阳性染色的部位主要为神经纤维分布的部位,包括苔状纤维,齿状回的颗粒细胞层外的分子层,而颗粒细胞层和锥体细胞层的胞体部位染色浅；皮层沉积老年斑内也可见SUMO-1的免疫阳性染色。12月龄野生型鼠SUMO-1在锥体细胞层淡染,颗粒细胞层较周围分布有神经纤维的部分染色更浅。
2.SD大鼠海马内注射Aβ,在不同的时间点应用ABC法检测SUMO-1表达和分布。结果显示：注入单体可溶性Aβ1-40后,SUMO-1在海马CA区锥体细胞层的表达随着时间的延长逐渐增加,在7天时表达最多；在注射纤维状Aβ1-40后注射部位附近的CA1区神经元有SUMO-1阳性染色,在7天时可以观察到在注射部位周围类似瘢痕组织的结构附近有较多的SUMO-1阳性纤维。同时也观察到在注射后的不同时间点皮层内有散在的团块状SUMO-1阳性染色。
3.昆明鼠的冷水应激后观察到Aβ免疫荧光染色增强。免疫组化和Western-blot技术检测显示,在应激12小时后脑内SUMO-1表达显著增加。正常动物SUMO-1主要分布在海马锥体细胞和齿状回内颗粒细胞的胞体,但染色较淡；在应激后海马脑片SUMO-1染色显著加深,免疫阳性物质主要分布在海马齿状回分子层、苔状纤维以及CA区放射层的区域。
综上所述,AD转基因动物海马内有c-fos和SUMO-1表达增加；不同浓度和肽段的Aβ短时间内可以诱导海马Fos表达增加并显示不同的分布模式,Aβ还可诱导NPY表达减少；Aβ可长时程诱导SUMO-1表达的改变。应激后脑内的有Aβ生成增加和SUMO-1表达增加,SUMO-1分布模式类似AD转基因动物。
The characteristic pathological changes of Alzheimer's disease (AD) include extracellular senile plaques formed by accumulated P-amyloid proteins(Aβ), the neurofibrillar tangles formed by abnormal phosphorylated tau, neuronal dystrophy and neuronal loss, neurotransmitter system impairment and so on. The exact etiological factor of AD is still unclear,but the neuronal toxicity of Aβis considered to identical factor in process of AD onset.In this experiment, we did some researches on exploring the possible effects of Aβon the expression of immediate early gene product c-Fos and posttranslational modifier small ubiquitin related-modifier (sumo-1). The main research results are as follows:
Part I
1.Using immunohistochemical staining, we found that there was a lot of senile plaques formed by accumulatedβ-amyloid proteins in the brain of 12 months transgenic mice with human APPswe and PS1 mutant (APPswe/PS1ΔAE9).The expression of Fos was increased with wildtype control and the Fos mainly distributed in cell body including pyramidal cell layer(PL) of hippocampus thalamus, hypothalamus and so on.
2.We injected different dose of soluble and fresh Aβ1-40 (2nmol,0.2nmol, 0.02nmol) into hippocampus. After three hours, the dose of 2nmol Aβ1-40 could induce the Fos expression in PL of hippocampus CA3/4, hilus and granular cells layer(GL) of gyrus dentate(DG),particularly in PL and hilus. In the dose of 0.2nml and 0.02nmol, we observed sporadic Fos immunopositive cells in hilus and GL near cerebral ventricle of DG. After six hours or longer time, the c-fos expression in hippocampus did not significantly change with control.
3. we injected Aβ1-28 and Aβ25-35. into hippocampus at dose of 2nmol.Three hours later, immunohistochemistry staing results showed that Fos immunopositive staining was increased in hilus and GL of DG near cerebral ventricle and PL of hippocampus CA3 but not obvious like Aβ1-40 group.The effects of Aβ25-35 on inducing Fos expression was more powerful than Aβ1-28.
4. We intracerebralventricularly injected Aβ1-40(0.02 nmol,0.2 nmol,2nmol). Three hours later,Fos positive staining chiefly distributed in the hilus and GL of DG and PL of hippocampus CA3. On brain slice of intracerebralventricular injection KA(1μg) three hours, Fos also were highly induced in the neuron of PL of hippocampus and GL of dentate gyrus. After six hours, the expression of Fos was decreased. we injected KA and Aβon the same time or KA and inhibitor of y-secreates that inhibited Aβgeneration, Fos expression and distribution was different from that was induced by KA.
5. We found that the NPY expression in the DG of rats that was injected 2nmol Aβ1-40 into hippocampus was lower than normal animal. We performed immuno-fluorescence double labeling and observed that Fos was partly colocalized with NPY. NPY expression was decreased accompanied by Fos enhanced, so there was less neuron that Fos colocalized with NPY.
PartⅡ
1. Immunohistochemical and immunoblot analysis revealed that the SUMO-1 expression of 12 months APPswe/PS1ΔE9 transgenic mice was increased with widetype control. The SUMO-1 positive staining were mainly localized in nerve fiber including mossy fiber and molecular layer out of GL of DG,but the staining of the PL and GL cell body was bland.Alternatively, there were SUMO-1 immunopositive senile plaque in cortex.In widetype mice, the SUMO-1 expression was lower in the PL and GL than the transgenic mouse. These showed that SUMO-1 may be related to AD.
2. We employed the Sprague-Dawley rats model that were injected different aggregation Aβ1-40 (soluble and fresh Aβ1-40 or fibril Aβ1-40) into hippocampus. After different injection time (1day,3days and 7days), using immunohistochemical staining we observered the Fos expression. In soluble and fresh group,the SUMO-1 positive cells were increased in the PL of hippocampus CA2/3 and were most on 7 days. In fibril group, there were SUMO-1 immunopositive neurons nearly injection region of hippocampus CA1 on the first day. On the seventh day, a lot of SUMO-1 immunopositive fiber distributed in the injection site. Interestingly, in the cortex and injection region,we also seen a little of clustered SIG on different time.
3. we confirmed that in the brain of cold stress mouse the expression of the Aβwas increased. the analyses immunohistochemical and immunoblot showed that SUMO-1 was bland staining in the body of PL of hippocampus CA1-3 region and GL of DG in normal animals. After cold stress the staining of SUMO-1 was increased in whole hippocampus and mainly distributed in molecular layer of DG, mossy fiber and stratum radiatum layer
In a word, Fos and SUMO-1 expression on the hippocampus of transgenic mouse was increased with widetype. Different dose and peptides Aβcould induce the expression and distribution change of Fos in a short time.Aβalso could induce SUMO-1 expression changed in long time. After cold stress, Aβand SUMO-1 expression was increased and the distribution of SUMO-1 was similar with the transgenic mouse.
引文
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30 Lozsadi DA, Lamer AJ. Prevalence and causes of seizures at the time of diagnosis of probable Alzheimer's disease. Dement Geriatr Cogn Disord, 2006,22:121-4.
31 Hauser WA, Morris ML, Heston LL, et al. Seizures and myoclonus in patients with Alzheimer's disease. Neurology,1986,36:1226-30.
32 Baraban SC. Neuropeptide Y and epilepsy:recent progress, prospects and controversies. Neuropeptides,2004,38:261-5.
33 Silva AP, Xapelli S, Pinheiro PS, et al. Up-regulation of neuropeptide Y levels and modulation of glutamate release through neuropeptide Y receptors in the hippocampus of kainate-induced epileptic rats. J Neurochem,2005,93:163-70.
34 Furtinger S, Pirker S, Czech T, et al. Plasticity of Y1 and Y2 receptors and neuropeptide Y fibers in patients with temporal lobe epilepsy. J Neurosci, 2001,21:5804-12.
35 Reibel S, Nadi S, Benmaamar R, et al. Neuropeptide Y and epilepsy:varying effects according to seizure type and receptor activation. Peptides, 2001,22:529-39.
36 Borges K, McDermott DL, Dingledine R. Reciprocal changes of CD44 and GAP-43 expression in the dentate gyrus inner molecular layer after status epilepticus in mice. Exp Neurol,2004,188:1-10.
37 Ramos B, Baglietto-Vargas D, del Rio JC, et al. Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1xAPP transgenic model of Alzheimer's disease. Neurobiol Aging,2006,27:1658-72.
38 Saitoh H, Hinchey J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem,2000,275:6252-8.
39 Guo D, Han J, Adam BL, et al. Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. Biochem Biophys Res Commun,2005,337:1308-18.
40 Tsurumaru M, Kawasaki E, Ida H, et al. Evidence for the role of small ubiquitin-like modifier 4 as a general autoimmunity locus in the Japanese population. J Clin Endocrinol Metab,2006,91:3138-43.
41 Schwartz DC, Hochstrasser M. A superfamily of protein tags:ubiquitin, SUMO and related modifiers. Trends Biochem Sci,2003,28:321-8.
42 Melchior F. SUMO--nonclassical ubiquitin. Annu Rev Cell Dev Biol, 2000,16:591-626.
43 Muller S, Hoege C, Pyrowolakis G, et al. SUMO, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol,2001,2:202-10.
44 Bernier-Villamor V, Sampson DA, Matunis MJ, et al. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAPl. Cell,2002,108:345-56.
45 Grace EA, Rabiner CA, Busciglio J. Characterization of neuronal dystrophy induced by fibrillar amyloid beta:implications for Alzheimer's disease. Neuroscience,2002,114:265-73.
46 Martin S, Nishimune A, Mellor JR, et al. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature,2007,447:321-5.
47 Shalizi A, Gaudilliere B, Yuan Z, et al. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science, 2006,311:1012-7.
48 Dadke S, Cotteret S, Yip SC, et al. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nat Cell Biol,2007,9:80-5.
49 Shirakura H, Hayashi N, Ogino S, et al. Caspase recruitment domain of procaspase-2 could be a target for SUMO-1 modification through Ubc9. Biochem Biophys Res Commun,2005,331:1007-15.
50 Yang W, Sheng H, Warner DS, et al. Transient global cerebral ischemia induces a massive increase in protein sumoylation. J Cereb Blood Flow Metab, 2008,28:269-79.
51 Shao R, Zhang FP, Tian F, et al. Increase of SUMO-1 expression in response to hypoxia:direct interaction with HIF-1 alpha in adult mouse brain and heart in vivo. FEBS Lett,2004,569:293-300.
52 Bossis G, Malnou CE, Farras R, et al. Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol,2005,25:6964-79.
1 Melchior F. SUMO--nonclassical ubiquitin. Annu Rev Cell Dev Biol, 2000,16:591-626.
2 Schwartz DC, Hochstrasser M. A superfamily of protein tags:ubiquitin, SUMO and related modifiers. Trends Biochem Sci,2003,28:321-8.
3 Mo YY, Yu Y, Shen Z, et al. Nucleolar delocalization of human topoisomerase I in response to topotecan correlates with sumoylation of the protein. J Biol Chem,2002,277:2958-64.
4 Mao Y, Sun M, Desai SD, et al. SUMO-1 conjugation to topoisomerase I:A possible repair response to topoisomerase-mediated DNA damage. Proc Natl Acad Sci U S A,2000,97:4046-51.
5 Guo D, Han J, Adam BL, et al. Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. Biochem Biophys Res Commun,2005,337:1308-18.
6 Saitoh H, Hinchey J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem,2000,275:6252-8.
7 Dohmen RJ. SUMO protein modification. Biochim Biophys Acta, 2004,1695:113-31.
8 Ciechanover A, Ben-Saadon R. N-terminal ubiquitination:more protein substrates join in. Trends Cell Biol,2004,14:103-6.
9 Tatham MH, Jaffray E, Vaughan OA, et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem,2001,276:35368-74.
10 Bernier-Villamor V, Sampson DA, Matunis MJ, et al. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell,2002,108:345-56.
11 Muller S, Hoege C, Pyrowolakis G, et al. SUMO, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol,2001,2:202-10.
12 Martin S, Nishimune A, Mellor JR, et al. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature,2007,447:321-5.
13 Lyons GE, Micales BK, Schwarz J, et al. Expression of mef2 genes in the mouse central nervous system suggests a role in neuronal maturation. J Neurosci,1995,15:5727-38.
14 McKinsey TA, Zhang CL, Olson EN. MEF2:a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci,2002,27:40-7.
15 Shalizi AK, Bonni A. Brawn for Brains:The Role of MEF2 Proteins in the Developing Nervous System. Curr Top Dev Biol,2005,69:239-66.
16 Mao Z, Bonni A, Xia F, et al. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science,1999,286:785-90.
17 Heidenreich KA, Linseman DA. Myocyte enhancer factor-2 transcription factors in neuronal differentiation and survival. Mol Neurobiol, 2004,29:155-66.
18 Shalizi A, Gaudilliere B, Yuan Z, et al. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science, 2006,311:1012-7.
19 Gong X, Tang X, Wiedmann M, et al. Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron,2003,38:33-46.
20 Zhu B, Gulick T. Phosphorylation and alternative pre-mRNA splicing converge to regulate myocyte enhancer factor 2C activity. Mol Cell Biol, 2004,24:8264-75.
21 Gregoire S, Yang XJ. Association with class Ⅱa histone deacetylases upregulates the sumoylation of MEF2 transcription factors. Mol Cell Biol, 2005,25:2273-87.
22 Dadke S, Cotteret S, Yip SC, et al. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nat Cell Biol,2007,9:80-5.
23 Li Y, Wang H, Wang S, et al. Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci U S A,2003,100:259-64.
24 Shimura H, Schwartz D, Gygi SP, et al. CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem, 2004,279:4869-76.
25 Petrucelli L, Dickson D, Kehoe K, et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet,2004,13:703-14.
26 Babu JR, Geetha T, Wooten MW. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem, 2005,94:192-203.
27 Bennett MC, Bishop JF, Leng Y, et al. Degradation of alpha-synuclein by proteasome. J Biol Chem,1999,274:33855-8.
28 David DC, Layfield R, Serpell L, et al. Proteasomal degradation of tau protein. J Neurochem,2002,83:176-85.
29 Tofaris GK, Layfield R, Spillantini MG. alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett,2001,509:22-6.
30 Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem,1984,259:5301-5.
31 Kimber TE, Blumbergs PC, Rice JP, et al. Familial neuronal intranuclear inclusion disease with ubiquitin positive inclusions. J Neurol Sci, 1998,160:33-40.
32 Quilty MC, King AE, Gai WP, et al. Alpha-synuclein is upregulated in neurones in response to chronic oxidative stress and is associated with neuroprotection. Exp Neurol,2006,199:249-56.
33 Lindenberg R, Rubinstein LJ, Herman MM, et al. A light and electron microscopy study of an unusual widespread nuclear inclusion body disease. A possible residuum of an old herpesvirus infection. Acta Neuropathol, 1968,10:54-73.
34 Haltia M, Tarkkanen A, Somer H, et al. Neuronal intranuclear inclusion disease. Clinical ophthalmological features and ophthalmic pathology. Acta Ophthalmol (Copenh),1986,64:637-43.
35 Pountney DL, Huang Y, Burns RJ, et al. SUMO-1 marks the nuclear inclusions in familial neuronal intranuclear inclusion disease. Exp Neurol, 2003,184:436-46.
36 Valentine JS, Doucette PA, Zittin Potter S. Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis. Annu Rev Biochem,2005,74:563-93.
37 Watanabe M, Dykes-Hoberg M, Culotta VC, et al. Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis,2001,8:933-41.
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45 Chung KK, Zhang Y, Lim KL, et al. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1:implications for Lewy-body formation in Parkinson disease. Nat Med,2001,7:1144-50.
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52 Ueda H, Goto J, Hashida H, et al. Enhanced SUMOylation in polyglutamine diseases. Biochem Biophys Res Commun,2002,293:307-13.
53 Shirakura H, Hayashi N, Ogino S, et al. Caspase recruitment domain of procaspase-2 could be a target for SUMO-1 modification through Ubc9. Biochem Biophys Res Commun,2005,331:1007-15.
54 Naoko H, Hiromi S, Takashi U, et al.Relationship between SUMO-1 modification of caspase-7 and its nuclear localization in human neuronal cells.Neuro Lett,2006 397:5-9
55 Yang W, Sheng H, Warner DS, et al. Transient global cerebral ischemia induces a massive increase in protein sumoylation. J Cereb Blood Flow Metab, 2008,28:269-79.
56 Shao R, Zhang FP, Tian F, et al. Increase of SUMO-1 expression in response to hypoxia:direct interaction with HIF-1alpha in adult mouse brain and heart in vivo. FEBS Lett,2004,569:293-300.
57 Dorval V, Mazzella MJ, Mathews PM, Modulation of Abeta generation by small ubiquitin-like modifiers does not require conjugation to target proteins. Biochem J.2007404(2):309-16.
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27 Chen Q, Nakajima A, Choi SH, et al. Adult neurogenesis is functionally associated with AD-like neurodegeneration. Neurobiol Dis,2008,29:316-26.
28 Palop JJ, Jones B, Kekonius L, et al. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci U S A,2003,100:9572-7.
29 Amatniek JC, Hauser WA, DelCastillo-Castaneda C, et al. Incidence and predictors of seizures in patients with Alzheimer's disease. Epilepsia, 2006,47:867-72.
30 Lozsadi DA, Lamer AJ. Prevalence and causes of seizures at the time of diagnosis of probable Alzheimer's disease. Dement Geriatr Cogn Disord, 2006,22:121-4.
31 Hauser WA, Morris ML, Heston LL, et al. Seizures and myoclonus in patients with Alzheimer's disease. Neurology,1986,36:1226-30.
32 Baraban SC. Neuropeptide Y and epilepsy:recent progress, prospects and controversies. Neuropeptides,2004,38:261-5.
33 Silva AP, Xapelli S, Pinheiro PS, et al. Up-regulation of neuropeptide Y levels and modulation of glutamate release through neuropeptide Y receptors in the hippocampus of kainate-induced epileptic rats. J Neurochem,2005,93:163-70.
34 Furtinger S, Pirker S, Czech T, et al. Plasticity of Y1 and Y2 receptors and neuropeptide Y fibers in patients with temporal lobe epilepsy. J Neurosci, 2001,21:5804-12.
35 Reibel S, Nadi S, Benmaamar R, et al. Neuropeptide Y and epilepsy:varying effects according to seizure type and receptor activation. Peptides, 2001,22:529-39.
36 Borges K, McDermott DL, Dingledine R. Reciprocal changes of CD44 and GAP-43 expression in the dentate gyrus inner molecular layer after status epilepticus in mice. Exp Neurol,2004,188:1-10.
37 Ramos B, Baglietto-Vargas D, del Rio JC, et al. Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1xAPP transgenic model of Alzheimer's disease. Neurobiol Aging,2006,27:1658-72.
38 Saitoh H, Hinchey J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem,2000,275:6252-8.
39 Guo D, Han J, Adam BL, et al. Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. Biochem Biophys Res Commun,2005,337:1308-18.
40 Tsurumaru M, Kawasaki E, Ida H, et al. Evidence for the role of small ubiquitin-like modifier 4 as a general autoimmunity locus in the Japanese population. J Clin Endocrinol Metab,2006,91:3138-43.
41 Schwartz DC, Hochstrasser M. A superfamily of protein tags:ubiquitin, SUMO and related modifiers. Trends Biochem Sci,2003,28:321-8.
42 Melchior F. SUMO--nonclassical ubiquitin. Annu Rev Cell Dev Biol, 2000,16:591-626.
43 Muller S, Hoege C, Pyrowolakis G, et al. SUMO, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol,2001,2:202-10.
44 Bernier-Villamor V, Sampson DA, Matunis MJ, et al. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAPl. Cell,2002,108:345-56.
45 Grace EA, Rabiner CA, Busciglio J. Characterization of neuronal dystrophy induced by fibrillar amyloid beta:implications for Alzheimer's disease. Neuroscience,2002,114:265-73.
46 Martin S, Nishimune A, Mellor JR, et al. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature,2007,447:321-5.
47 Shalizi A, Gaudilliere B, Yuan Z, et al. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science, 2006,311:1012-7.
48 Dadke S, Cotteret S, Yip SC, et al. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nat Cell Biol,2007,9:80-5.
49 Shirakura H, Hayashi N, Ogino S, et al. Caspase recruitment domain of procaspase-2 could be a target for SUMO-1 modification through Ubc9. Biochem Biophys Res Commun,2005,331:1007-15.
50 Yang W, Sheng H, Warner DS, et al. Transient global cerebral ischemia induces a massive increase in protein sumoylation. J Cereb Blood Flow Metab, 2008,28:269-79.
51 Shao R, Zhang FP, Tian F, et al. Increase of SUMO-1 expression in response to hypoxia:direct interaction with HIF-1 alpha in adult mouse brain and heart in vivo. FEBS Lett,2004,569:293-300.
52 Bossis G, Malnou CE, Farras R, et al. Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol,2005,25:6964-79.
1 Melchior F. SUMO--nonclassical ubiquitin. Annu Rev Cell Dev Biol, 2000,16:591-626.
2 Schwartz DC, Hochstrasser M. A superfamily of protein tags:ubiquitin, SUMO and related modifiers. Trends Biochem Sci,2003,28:321-8.
3 Mo YY, Yu Y, Shen Z, et al. Nucleolar delocalization of human topoisomerase I in response to topotecan correlates with sumoylation of the protein. J Biol Chem,2002,277:2958-64.
4 Mao Y, Sun M, Desai SD, et al. SUMO-1 conjugation to topoisomerase I:A possible repair response to topoisomerase-mediated DNA damage. Proc Natl Acad Sci U S A,2000,97:4046-51.
5 Guo D, Han J, Adam BL, et al. Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. Biochem Biophys Res Commun,2005,337:1308-18.
6 Saitoh H, Hinchey J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem,2000,275:6252-8.
7 Dohmen RJ. SUMO protein modification. Biochim Biophys Acta, 2004,1695:113-31.
8 Ciechanover A, Ben-Saadon R. N-terminal ubiquitination:more protein substrates join in. Trends Cell Biol,2004,14:103-6.
9 Tatham MH, Jaffray E, Vaughan OA, et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem,2001,276:35368-74.
10 Bernier-Villamor V, Sampson DA, Matunis MJ, et al. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell,2002,108:345-56.
11 Muller S, Hoege C, Pyrowolakis G, et al. SUMO, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol,2001,2:202-10.
12 Martin S, Nishimune A, Mellor JR, et al. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature,2007,447:321-5.
13 Lyons GE, Micales BK, Schwarz J, et al. Expression of mef2 genes in the mouse central nervous system suggests a role in neuronal maturation. J Neurosci,1995,15:5727-38.
14 McKinsey TA, Zhang CL, Olson EN. MEF2:a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci,2002,27:40-7.
15 Shalizi AK, Bonni A. Brawn for Brains:The Role of MEF2 Proteins in the Developing Nervous System. Curr Top Dev Biol,2005,69:239-66.
16 Mao Z, Bonni A, Xia F, et al. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science,1999,286:785-90.
17 Heidenreich KA, Linseman DA. Myocyte enhancer factor-2 transcription factors in neuronal differentiation and survival. Mol Neurobiol, 2004,29:155-66.
18 Shalizi A, Gaudilliere B, Yuan Z, et al. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science, 2006,311:1012-7.
19 Gong X, Tang X, Wiedmann M, et al. Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron,2003,38:33-46.
20 Zhu B, Gulick T. Phosphorylation and alternative pre-mRNA splicing converge to regulate myocyte enhancer factor 2C activity. Mol Cell Biol, 2004,24:8264-75.
21 Gregoire S, Yang XJ. Association with class Ⅱa histone deacetylases upregulates the sumoylation of MEF2 transcription factors. Mol Cell Biol, 2005,25:2273-87.
22 Dadke S, Cotteret S, Yip SC, et al. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nat Cell Biol,2007,9:80-5.
23 Li Y, Wang H, Wang S, et al. Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci U S A,2003,100:259-64.
24 Shimura H, Schwartz D, Gygi SP, et al. CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem, 2004,279:4869-76.
25 Petrucelli L, Dickson D, Kehoe K, et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet,2004,13:703-14.
26 Babu JR, Geetha T, Wooten MW. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem, 2005,94:192-203.
27 Bennett MC, Bishop JF, Leng Y, et al. Degradation of alpha-synuclein by proteasome. J Biol Chem,1999,274:33855-8.
28 David DC, Layfield R, Serpell L, et al. Proteasomal degradation of tau protein. J Neurochem,2002,83:176-85.
29 Tofaris GK, Layfield R, Spillantini MG. alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett,2001,509:22-6.
30 Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem,1984,259:5301-5.
31 Kimber TE, Blumbergs PC, Rice JP, et al. Familial neuronal intranuclear inclusion disease with ubiquitin positive inclusions. J Neurol Sci, 1998,160:33-40.
32 Quilty MC, King AE, Gai WP, et al. Alpha-synuclein is upregulated in neurones in response to chronic oxidative stress and is associated with neuroprotection. Exp Neurol,2006,199:249-56.
33 Lindenberg R, Rubinstein LJ, Herman MM, et al. A light and electron microscopy study of an unusual widespread nuclear inclusion body disease. A possible residuum of an old herpesvirus infection. Acta Neuropathol, 1968,10:54-73.
34 Haltia M, Tarkkanen A, Somer H, et al. Neuronal intranuclear inclusion disease. Clinical ophthalmological features and ophthalmic pathology. Acta Ophthalmol (Copenh),1986,64:637-43.
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