Glial S100B protein modulates mutant ataxin-1 aggregation and toxicity: TRTK12 peptide, a potential candidate for SCA1 therapy.
Glial S100B protein modulates mutant ataxin-1 aggregation and toxicity: TRTK12 peptide, a potential candidate for SCA1 therapy.
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DOI：
10.1007/s12311-011-0262-5
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发表时间：
2011-06
期刊：
影响因子：
3.5
通讯作者：
Safaya, Eshan
中科院分区：
文献类型：
--
作者：
Vig, Parminder J. S.;Hearst, Scoty;Shao, Qingmei;Lopez, Mariper E.;Murphy, Henry A., II;Safaya, Eshan
关键词：
神经胶质细胞在多聚谷氨酰胺疾病发病机制中的非细胞自主参与在共济失调领域得到了认可。我们以前证明，浦肯野细胞（PC）在多聚谷氨酰胺疾病脊髓小脑共济失调-1（SCA 1）含有胞质空泡丰富的Bergmann神经胶质（BG）蛋白S100 B。SCA 1细胞中空泡的形成伴随着树突棘的异常形态。此外，S100 B mRNA表达水平显着高，在小脑的无症状SCA 1转基因（Tg）小鼠，并进一步增加与年龄匹配的野生型动物相比，随着年龄的增长。这种较高的S100 B mRNA表达与空泡数量的增加呈正相关。为了进一步表征S100 B在SCA 1病理学中的功能，我们在HEK稳定细胞系中探索了S100 B蛋白对具有扩增的聚谷氨酰胺[82 Q]的GFP-共济失调蛋白-1（ATXN 1）的影响。向这些细胞中外部添加S100 B蛋白诱导S100 B阳性空泡，类似于在体内SCA 1 PC中所观察到的空泡。此外，我们发现外部添加和内部表达的S100 B均显著减少GFP-ATXN 1 [82 Q]包涵体形成。相反，添加S100 B抑制肽TRTK 12逆转了S100 B介导的效应。有趣的是，在SCA 1 Tg小鼠中，含有S100 B空泡的PC也显示缺乏核包涵体，而没有空泡的PC含有核包涵体。此外，TRTK 12处理减少了从SCA 1 Tg小鼠制备的小脑切片培养物中PC的异常树突生长和形态。此外，鼻内给予SCA 1 Tg小鼠TRTK 12降低了颗粒级分中的小脑S100 B水平，并且这些小鼠在转棒测试中表现出显著改善。综上所述，我们的研究结果表明，胶质细胞S100 B可能通过调节突变型共济失调蛋白-1的毒性/溶解度，通过一个未知的信号转导途径，增加SCA 1 PC的退行性变化。
Non-cell autonomous involvement of glial cells in the pathogenesis of polyglutamine diseases is gaining recognition in the ataxia field. We previously demonstrated that Purkinje cells (PCs) in polyglutamine disease spinocerebellar ataxia-1 (SCA1) contain cytoplasmic vacuoles rich in Bergmann glial (BG) protein S100B. The vacuolar formation in SCA1 PCs is accompanied with an abnormal morphology of dendritic spines. In addition, S100B mRNA expression levels are significantly high in the cerebella of asymptomatic SCA1 transgenic (Tg) mice and increase further with age when compared with the age-matched wildtype animals. This higher S100B mRNA expression positively correlates with an increase in the number of vacuoles. To further characterize the function of S100B in SCA1 pathology, we explored the effects of S100B protein on GFP-ataxin-1 (ATXN1) with expanded polyglutamines [82Q] in HEK stable cell line. Externally added S100B protein to these cells induced S100B positive vacuoles similar to those seen in SCA1 PCs in vivo. Further, we found that both externally added and internally expressed S100B significantly reduced GFP-ATXN1[82Q] inclusion body formation. In contrast, the addition of S100B inhibitory peptide TRTK12 reversed S100B mediated effects. Interestingly, in SCA1 Tg mice, PCs containing S100B vacuoles also showed the lack of nuclear inclusions, whereas, PCs without vacuoles contained nuclear inclusions. Additionally, TRTK12 treatment reduced abnormal dendritic growth and morphology of PCs in cerebellar slice cultures prepared from SCA1 Tg mice. Moreover, intranasal administration of TRTK12 to SCA1 Tg mice reduced cerebellar S100B levels in the particulate fractions and these mice displayed a significant improvement in their performance deficit on the Rotarod test. Taken together our results suggest that glial S100B may augment degenerative changes in SCA1 PCs by modulating mutant ataxin-1 toxicity/solubility through an unknown signaling pathway.
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影响因子：
25
作者：
Lin, X;Antalffy, B;Zoghbi, HY
通讯作者：
Zoghbi, HY
影响因子：
3.5
作者：
Goold, Robert;Hubank, Michael;Matilla-Duenas, Antoni
通讯作者：
Matilla-Duenas, Antoni
影响因子：
4.7
作者：
Ellis, Earl F.;Willoughby, Karen A.;Chen, Tao
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通过 NMR 和 X 射线晶体学检查 CapZ 肽 (TRTK-12) 与 S100B-Ca2+ 结合的影响。
影响因子：
5.6
作者：
Charpentier TH;Thompson LE;Liriano MA;Varney KM;Wilder PT;Pozharski E;Toth EA;Weber DJ
通讯作者：
Weber DJ
影响因子：
4.7
作者：
Hearst, Scoty M.;Lopez, Mariper E.;Vig, Parminder J. S.
通讯作者：
Vig, Parminder J. S.