Protein Aggregation and Dysfunction of Autophagy-Lysosomal Pathway: A Vicious Cycle in Lysosomal Storage Diseases
Protein Aggregation and Dysfunction of Autophagy-Lysosomal Pathway: A Vicious Cycle in Lysosomal Storage Diseases
复制标题
DOI：
10.3389/fnmol.2020.00037
复制
发表时间：
2020-03-11
影响因子：
4.8
通讯作者：
Fraldi, Alessandro
中科院分区：
文献类型：
--
作者：
Monaco, Antonio;Fraldi, Alessandro
许多神经退行性疾病的特征是中枢神经系统(CNS)中蛋白质聚集体(主要是淀粉样蛋白)的沉积。在有丝分裂后的中枢神经系统细胞中，蛋白质聚集通过干扰多种细胞功能而引起细胞毒性。不同基因的突变可能直接导致蛋白质聚集。然而，遗传因素和衰老一起也可能通过影响细胞的降解功能，特别是自噬-溶酶体途径(ALP)来促进蛋白质聚集的开始。越来越多的证据表明，在神经退行性变过程中，碱性磷酸酶功能障碍和蛋白质聚集在功能上是相互联系和诱导的。我们将通过重点关注溶酶体储存疾病(LSD)来总结支持这些概念的发现，LSD是一类代谢遗传性疾病，以全球溶酶体功能障碍为特征，通常与严重的神经退行性变相关。我们提出了一个模型，在这个模型中，遗传性溶酶体缺陷引发易于聚集的蛋白质沉积，进而恶化ALP的降解功能，从而产生恶性循环，促进神经退行性变。
Many neurodegenerative conditions are characterized by the deposition of protein aggregates (mainly amyloid-like) in the central nervous system (CNS). In post-mitotic CNS cells protein aggregation causes cytotoxicity by interfering with various cellular functions. Mutations in different genes may directly cause protein aggregation. However, genetic factors together with aging may contribute to the onset of protein aggregation also by affecting cellular degradative functions, in particular the autophagy-lysosomal pathway (ALP). Increasing body of evidence show that ALP dysfunction and protein aggregation are functionally interconnected and induce each other during neurodegenerative processes. We will summarize the findings supporting these concepts by focusing on lysosomal storage diseases (LSDs), a class of metabolic inherited conditions characterized by global lysosomal dysfunction and often associated to a severe neurodegenerative course. We propose a model by which the inherited lysosomal defects initiate aggregate-prone protein deposition, which, in turns, worsen ALP degradation function, thus generating a vicious cycle, which boost neurodegenerative cascades.