Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy
Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy
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DOI：
10.1093/hmg/ddg293
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发表时间：
2003-10-15
影响因子：
3.5
通讯作者：
Rouleau, GA
中科院分区：
文献类型：
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作者：
Abu-Baker, A;Messaed, C;Rouleau, GA
眼咽肌营养不良症 (OPMD) 是一种迟发性常染色体显性肌营养不良症，由 PABPN1 基因中的聚丙氨酸束小幅扩张所致。核内包涵体是 OPMD 的病理标志。 OPMD 中蛋白质聚集可能与毒性功能获得相关的机制迄今仍不清楚。蛋白质聚集体本身是否具有致病性，或者是未知的潜在分子机制的结果，目前仍不清楚。在这里，我们报告 OPMD 细胞模型中的蛋白质聚集直接损害泛素蛋白酶体途径 (UPP) 的功能以及分子伴侣功能。蛋白酶体抑制剂乳胞素会导致蛋白质聚集和毒性显着增加。此外，分子伴侣（HSP40和HSP70）的过度表达抑制了蛋白质聚集和毒性。我们还提供了 mPABPN1-ala17 蛋白聚集与毒性成比例相关的证据。此外，我们表明，OPMD 细胞模型中伴侣蛋白的共表达增加了 mPABPN1-ala17 的溶解度和转染细胞的存活率。我们的研究表明，多聚丙氨酸蛋白质溶解度和降解的分子调节剂可能为 OPMD 发病机制的新机制提供见解。进一步分析 UPP 和分子伴侣影响错误折叠蛋白降解的细胞和分子机制，可以为治疗和理解 OPMD 和神经退行性疾病的发病机制提供新的概念和靶点。
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy that results from small expansions of a polyalanine tract in the PABPN1 gene. Intranuclear inclusions are the pathological hallmark of OPMD. The mechanism by which protein aggregation in OPMD might relate to a toxic gain-of-function has so far remained elusive. Whether protein aggregates themselves are pathogenic or are the consequence of an unidentified underlying molecular mechanism is still unclear. Here, we report that protein aggregation in a cell model of OPMD directly impaires the function of the ubiquitin-proteasome pathway (UPP) as well as molecular chaperone functions. The proteasome inhibitor lactacystin causes significant increase of protein aggregation and toxicity. Moreover, overexpression of molecular chaperones (HSP40 and HSP70) suppressed protein aggregation and toxicity. We also provide evidence that mPABPN1-ala17 protein aggregation proportionally correlates with toxicity. Furthermore, we show that co-expression of chaperones in our OPMD cell model increases the solubility of mPABPN1-ala17 and transfected cell survival rate. Our studies suggest that molecular regulators of polyalanine protein solubility and degradation may provide insights into new mechanisms in OPMD pathogenesis. Further analysis of the cellular and molecular mechanisms by which UPP and molecular chaperones influence the degradation of misfolded proteins could provide novel concepts and targets for the treatment and understanding of the pathogenesis of OPMD and neurodegenerative diseases.