Alpha-synuclein, Proteotoxicity and Parkinson's Disease: Search for Neuroprotective Therapy.
Alpha-synuclein, Proteotoxicity and Parkinson's Disease: Search for Neuroprotective Therapy.
复制标题
DOI：
10.2174/1570159x15666171129100944
复制
发表时间：
2018
影响因子：
5.3
通讯作者：
Chakrabarti S
中科院分区：
文献类型：
--
作者：
Ganguly U;Chakrabarti SS;Kaur U;Mukherjee A;Chakrabarti S
在帕金森病（PD）的动物和细胞模型中有越来越多的证据表明α-突触核蛋白的过度表达和/或异常积累和聚集可触发神经元死亡。α-突触核蛋白在PD发病机制中的重要作用得到以下事实的支持：α-突触核蛋白基因的重复、三倍和突变导致家族性PD。通过检索PubMed和Google Scholar进行文献综述，以查找强调α-突触核蛋白的致病作用以及靶向与该蛋白相关的各种途径的潜在治疗意义的相关文章。α-突触核蛋白在神经元内的过度表达和积累可能涉及转录和转录后机制，包括通过蛋白酶体或自噬过程减少蛋白质的降解。单体α-突触核蛋白聚集成寡聚体和原纤维的机制已被深入研究，但仍不确定这种天然未折叠蛋白的哪种形式是毒性的原因。同样，α-突触核蛋白诱导的蛋白毒性途径导致神经元死亡尚未完全阐明，但线粒体功能障碍、内质网（ER）应激和改变的ER-高尔基体转运可能在此过程中起关键作用。在分子水平上，α-突触核蛋白在生物膜中形成孔或与细胞器和胞质溶胶的特定蛋白质相互作用的能力可能是该蛋白质毒性的决定因素。尽管我们目前对α-突触核蛋白的生理和病理功能的认识存在许多局限性，但似乎这种蛋白质可能是开发针对PD的神经保护药物的靶点。本文综述了在不同的实验模型中，通过抑制α-synuclein的表达、蓄积和聚集，或抑制其与线粒体或内质网的相互作用，从而有效地消除α-synuclein介导的毒性作用的药物。
There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms of PD. A review of literature was performed by searching PubMed and Google Scholar for relevant articles highlighting the pathogenic role of α-synuclein and the potential therapeutic implications of targeting various pathways related to this protein. The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional and post-transcriptional mechanisms including a decreased degradation of the protein through proteasomal or autophagic processes. The mechanisms of monomeric α-synuclein aggregating to oligomers and fibrils have been investigated intensively, but it is still not certain which form of this natively unfolded protein is responsible for toxicity. Likewise the proteotoxic pathways induced by α-synuclein leading to neuronal death are not elucidated completely but mitochondrial dysfunction, endoplasmic reticulum (ER) stress and altered ER-golgi transport may play crucial roles in this process. At the molecular level, the ability of α-synuclein to form pores in biomembranes or to interact with specific proteins of the cell organelles and the cytosol could be determining factors in the toxicity of this protein. Despite many limitations in our present knowledge of physiological and pathological functions of α-synuclein, it appears that this protein may be a target for the development of neuroprotective drugs against PD. This review has discussed many such potential drugs which prevent the expression, accumulation and aggregation of α-synuclein or its interactions with mitochondria or ER and thereby effectively abolish α-synuclein mediated toxicity in different experimental models.