Sorbonne Universités, UPMC Univ. Paris 6, ICM, 75013, Paris, France,
Acta Neuropathol. 2014 Nov;128(5):705-22. doi: 10.1007/s00401-014-1289-8. Epub 2014 May 24.
There is still no treatment for polyglutamine disorders, but clearance of mutant proteins might represent a potential therapeutic strategy. Autophagy, the major pathway for organelle and protein turnover, has been implicated in these diseases. To determine whether the autophagy/lysosome system contributes to the pathogenesis of spinocerebellar ataxia type 7 (SCA7), caused by expansion of a polyglutamine tract in the ataxin-7 protein, we looked for biochemical, histological and transcriptomic abnormalities in components of the autophagy/lysosome pathway in a knock-in mouse model of the disease, postmortem brain and peripheral blood mononuclear cells (PBMC) from patients. In the mouse model, mutant ataxin-7 accumulated in inclusions immunoreactive for the autophagy-associated proteins mTOR, beclin-1, p62 and ubiquitin. Atypical accumulations of the autophagosome/lysosome markers LC3, LAMP-1, LAMP2 and cathepsin-D were also found in the cerebellum of the SCA7 knock-in mice. In patients, abnormal accumulations of autophagy markers were detected in the cerebellum and cerebral cortex of patients, but not in the striatum that is spared in SCA7, suggesting that autophagy might be impaired by the selective accumulation of mutant ataxin-7. In vitro studies demonstrated that the autophagic flux was impaired in cells overexpressing full-length mutant ataxin-7. Interestingly, the expression of the early autophagy-associated gene ATG12 was increased in PBMC from SCA7 patients in correlation with disease severity. These results provide evidence that the autophagy/lysosome pathway is impaired in neurons undergoing degeneration in SCA7. Autophagy/lysosome-associated molecules might, therefore, be useful markers for monitoring the effects of potential therapeutic approaches using modulators of autophagy in SCA7 and other autophagy/lysosome-associated neurodegenerative disorders.
目前尚无治疗多聚谷氨酰胺疾病的方法，但清除突变蛋白可能代表一种潜在的治疗策略。自噬是细胞器和蛋白质周转的主要途径，与这些疾病有关。为了确定自噬/溶酶体系统是否有助于由ataxin-7 蛋白中多聚谷氨酰胺片段扩展引起的脊髓小脑共济失调 7 型（SCA7）的发病机制，我们研究了疾病的敲入小鼠模型、死后大脑和外周血单核细胞（PBMC）中自噬/溶酶体途径成分的生化、组织学和转录组学异常从患者。在小鼠模型中，突变ataxin-7 在与自噬相关的蛋白 mTOR、beclin-1、p62 和泛素的免疫反应性包含物中积累。在 SCA7 敲入小鼠的小脑中还发现了自噬体/溶酶体标记物 LC3、LAMP-1、LAMP2 和组织蛋白酶-D 的非典型积累。在患者中，在患者的小脑和大脑皮层中检测到自噬标记物的异常积累，但在 SCA7 中未受累的纹状体中未检测到，这表明自噬可能因突变ataxin-7 的选择性积累而受损。体外研究表明，在过度表达全长突变 ataxin-7 的细胞中，自噬流受损。有趣的是，在 SCA7 患者的 PBMC 中，与疾病严重程度相关的早期自噬相关基因 ATG12 的表达增加。这些结果为自噬/溶酶体途径在 SCA7 神经元退行性变中受损提供了证据。因此，自噬/溶酶体相关分子可能是监测使用自噬调节剂在 SCA7 和其他自噬/溶酶体相关神经退行性疾病中潜在治疗方法效果的有用标记物。
