Activating Autophagy as a Therapeutic Strategy for Parkinson's Disease
Activating Autophagy as a Therapeutic Strategy for Parkinson's Disease
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DOI：
10.1007/s40263-018-0497-5
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发表时间：
2018-01-01
期刊：
影响因子：
6
通讯作者：
Moussa, Charbel E. -H.
中科院分区：
文献类型：
--
作者：
Fowler, Alan J.;Moussa, Charbel E. -H.
帕金森病是一种以路易体病理为特征的进行性神经退行性疾病，其主要成分是聚集的错误折叠的α-突触核蛋白。目前，尚无针对潜在的 α-突触核蛋白功能障碍和积累的临床疗法，帕金森病患者的护理标准仅侧重于症状管理，造成了需要填补的巨大治疗空白。自噬缺陷与帕金森病密切相关。在这里，我们回顾了来自人类、小鼠和细胞培养研究的证据，简要解释了帕金森病中自噬的这些缺陷，以及仔细、精确地调整自噬以维持神经元存活的必要性。我们总结了最近用于治疗 α-突触核蛋白帕金森病和相关突触核蛋白病中 α-突触核蛋白积累的实验药物。开发实验药物的大部分努力都集中在免疫治疗策略上，但我们讨论了为什么这些努力是错误的。最后，我们强调为什么增加α-突触核蛋白清除的自噬通量是最有前途的治疗策略。激活自噬已在帕金森病的临床前模型中取得成功，并在临床试验中产生了有希望的结果。
Parkinson's disease is a progressive neurodegenerative disease characterized by Lewy body pathology of which the primary constituent is aggregated misfolded alpha-synuclein protein. Currently, there are no clinical therapies for treatment of the underlying alpha-synuclein dysfunction and accumulation, and the standard of care for patients with Parkinson's disease focuses only on symptom management, creating an immense therapeutic gap that needs to be filled. Defects in autophagy have been strongly implicated in Parkinson's disease. Here, we review evidence from human, mouse, and cell culture studies to briefly explain these defects in autophagy in Parkinson's disease and the necessity for autophagy to be carefully and precisely tuned to maintain neuron survival. We summarize recent experimental agents for treating alpha-synuclein accumulation in alpha-synuclein Parkinson's disease and related synucleinopathies. Most of the efforts for developing experimental agents have focused on immunotherapeutic strategies, but we discuss why those efforts are misplaced. Finally, we emphasize why increasing autophagy flux for alpha-synuclein clearance is the most promising therapeutic strategy. Activating autophagy has been successful in preclinical models of Parkinson's disease and yields promising results in clinical trials.