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A Cleaning Crew: The Pursuit of Autophagy in Parkinson's Disease.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2019-08-20 , DOI: 10.1021/acschemneuro.9b00244 Pathik Parekh 1 , Nishant Sharma 1 , Anagha Gadepalli 1 , Abhishekh Shahane 1 , Monika Sharma 1 , Amit Khairnar 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2019-08-20 , DOI: 10.1021/acschemneuro.9b00244 Pathik Parekh 1 , Nishant Sharma 1 , Anagha Gadepalli 1 , Abhishekh Shahane 1 , Monika Sharma 1 , Amit Khairnar 1
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Parkinson's disease (PD) is the second-most common neurodegenerative disorder, neuropathologically characterized by the aggregation of misfolded α-synuclein (α-syn) protein, which appears to be central to the onset and progression of PD pathology. Evidence from pioneering studies has highly advocated the existence of impaired autophagy pathways in the brains of PD patients. Autophagy is an evolutionarily conserved, homeostatic mechanism for minimizing abnormal protein aggregates and facilitating organelle turnover. Any aberration in constitutive autophagy activity results in the aggregation of misfolded α-syn, which, in turn, may further inhibit their own degradation-leading to a vicious cycle of neuronal death. Despite the plethora of available literature, there are still lacunas existing in our understanding of the exact cellular interplay between autophagy impairment and α-syn accumulation-mediated neurotoxicity. In this context, clearance of aggregated α-syn via up-regulation of the autophagy-lysosomal pathway could provide a pharmacologically viable approach to the treatment of PD. The present Review highlights the basics of autophagy and detrimental cross-talk between α-syn and chaperone-mediated autophagy, and α-syn and macroautophagy. It also depicts the interaction between α-syn and novel targets, LRRK2 and mTOR, followed by the role of autophagy in PD from a therapeutic perspective. More importantly, it further updates the reader's understanding of various newer therapeutic avenues that may accomplish disease modification via promoting clearance of toxic α-syn through activation of autophagy.
中文翻译：
清洁人员：自噬在帕金森氏病中的追求。
帕金森氏病（PD）是第二大常见神经退行性疾病，其神经病理学特征是错误折叠的α-突触核蛋白（α-syn）蛋白聚集，这似乎是PD病理起病和发展的关键。开创性研究的证据强烈主张PD患者大脑中自噬途径受损。自噬是一种进化保守的体内平衡机制，可最大程度地减少异常蛋白质聚集并促进细胞器更新。组成型自噬活性的任何异常都会导致错误折叠的α-syn聚集，进而可能进一步抑制其自身降解，从而导致神经元死亡的恶性循环。尽管有大量可用的文献，在我们对自噬损伤与α-syn积累介导的神经毒性之间确切的细胞相互作用的理解中，仍然存在着缺陷。在这种情况下，通过自噬-溶酶体途径的上调清除聚集的α-syn可以提供治疗PD的药理学可行方法。本综述重点介绍了α-syn和伴侣介导的自噬以及α-syn和巨自噬之间自噬和有害串扰的基础。它还从治疗角度描述了α-syn与新型靶标LRRK2和mTOR之间的相互作用，以及自噬在PD中的作用。更重要的是，它进一步更新了读者的
更新日期：2019-08-06
中文翻译：
清洁人员：自噬在帕金森氏病中的追求。
帕金森氏病（PD）是第二大常见神经退行性疾病，其神经病理学特征是错误折叠的α-突触核蛋白（α-syn）蛋白聚集，这似乎是PD病理起病和发展的关键。开创性研究的证据强烈主张PD患者大脑中自噬途径受损。自噬是一种进化保守的体内平衡机制，可最大程度地减少异常蛋白质聚集并促进细胞器更新。组成型自噬活性的任何异常都会导致错误折叠的α-syn聚集，进而可能进一步抑制其自身降解，从而导致神经元死亡的恶性循环。尽管有大量可用的文献，在我们对自噬损伤与α-syn积累介导的神经毒性之间确切的细胞相互作用的理解中，仍然存在着缺陷。在这种情况下，通过自噬-溶酶体途径的上调清除聚集的α-syn可以提供治疗PD的药理学可行方法。本综述重点介绍了α-syn和伴侣介导的自噬以及α-syn和巨自噬之间自噬和有害串扰的基础。它还从治疗角度描述了α-syn与新型靶标LRRK2和mTOR之间的相互作用，以及自噬在PD中的作用。更重要的是，它进一步更新了读者的
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