A Charcot-Marie-Tooth-Causing Mutation in HSPB1 Decreases Cell Adaptation to Repeated Stress by Disrupting Autophagic Clearance of Misfolded Proteins.
A Charcot-Marie-Tooth-Causing Mutation in HSPB1 Decreases Cell Adaptation to Repeated Stress by Disrupting Autophagic Clearance of Misfolded Proteins.
复制标题
HSPB1 中夏科-玛丽-图思引起的突变通过破坏错误折叠蛋白的自噬清除来降低细胞对重复应激的适应
作者：
夏科-玛丽-图斯(Charcot-Marie-Tooth，CMT)病是一种最常见的遗传性神经退行性疾病，伴有选择性周围神经变性。尽管在识别CMT致病基因方面取得了进展，但其潜在的分子机制，特别是周围神经元选择性变性的分子机制仍有待阐明。由于外周神经元对多重应激敏感，我们推测日常重复应激可能是CMT引起的突变导致的外周神经元选择性变性的重要因素。在此，我们主要研究了27 kDa小分子热休克蛋白HSPB1中显性错义突变(S135F)在重复热休克条件下的生物学效应。与野生型相比，HSPB1S135F在重复热休克过程中表现出与α-微管蛋白和乙酰化α-微管蛋白的高度结合。与微管蛋白的异常相互作用阻止了基于微管的热休克诱导的错误折叠蛋白的运输，以形成核周侵袭体。此外，自噬小体沿微管的运输也被阻断。这些结果表明，自噬途径被破坏，导致泛素化的蛋白质聚集体积累，细胞对重复应激的适应显著降低。我们的发现为HSPB1S135F诱导的外周神经元选择性变性的分子机制提供了新的见解，并为靶向自噬作为CMT神经病的一种有前途的治疗策略提供了前景。
Charcot-Marie-Tooth (CMT) disease is the most common inherited neurodegenerative disorder with selective degeneration of peripheral nerves. Despite advances in identifying CMT-causing genes, the underlying molecular mechanism, particularly of selective degeneration of peripheral neurons remains to be elucidated. Since peripheral neurons are sensitive to multiple stresses, we hypothesized that daily repeated stress might be an essential contributor to the selective degeneration of peripheral neurons induced by CMT-causing mutations. Here, we mainly focused on the biological effects of the dominant missense mutation (S135F) in the 27-kDa small heat-shock protein HSPB1 under repeated heat shock. HSPB1S135F presented hyperactive binding to both α-tubulin and acetylated α-tubulin during repeated heat shock when compared with the wild type. The aberrant interactions with tubulin prevented microtubule-based transport of heat shock-induced misfolded proteins for the formation of perinuclear aggresomes. Furthermore, the transport of autophagosomes along microtubules was also blocked. These results indicate that the autophagy pathway was disrupted, leading to an accumulation of ubiquitinated protein aggregates and a significant decrease in cell adaptation to repeated stress. Our findings provide novel insights into the molecular mechanisms of HSPB1S135F-induced selective degeneration of peripheral neurons and perspectives for targeting autophagy as a promising therapeutic strategy for CMT neuropathy.
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影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
DOI：
10.1074/jbc.m109.082644
发表时间：
2010-04-23
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Almeida-Souza L;Goethals S;de Winter V;Dierick I;Gallardo R;Van Durme J;Irobi J;Gettemans J;Rousseau F;Schymkowitz J;Timmerman V;Janssens S
通讯作者：
Janssens S
影响因子：
5.6
作者：
Ko SH;Gonzalez G;Liu Z;Chen L
通讯作者：
Chen L
影响因子：
64.5
作者：
Buchan, J. Ross;Kolaitis, Regina-Maria;Parker, Roy
通讯作者：
Parker, Roy
影响因子：
82.9
作者：
d'Ydewalle, Constantin;Krishnan, Jyothsna;Van Den Bosch, Ludo
通讯作者：
Van Den Bosch, Ludo