Laboratory of Cellular and Molecular Neurobiology, IRCCS Mondino Foundation, Pavia, Italy.
Curr Med Chem. 2019;26(20):3702-3718. doi: 10.2174/0929867325666180226094351.
Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include macroautophagy, chaperone-mediated autophagy and microautophagy, each involving different mechanisms of substrate delivery to lysosome. Defects of these pathways and the resulting accumulation of protein aggregates represent a common pathobiological feature of neurodegenerative disorders such as Alzheimer, Parkinson and Huntington disease. This review provides an overview of the role of autophagy in Parkinson's disease (PD) by summarizing the most relevant genetic and experimental evidence showing how this process can contribute to disease pathogenesis. Given lysosomes take part in the final step of the autophagic process, the role of lysosomal defects in the impairment of autophagy and their impact on disease will also be discussed. A glance on the role of non-neuronal autophagy in the pathogenesis of PD will be included. Moreover, we will examine novel pharmacological targets and therapeutic strategies that, by boosting autophagy, may be theoretically beneficial for PD. Special attention will be focused on natural products, such as phenolic compounds, that are receiving increasing consideration due to their potential efficacy associated with low toxicity. Although many efforts have been made to elucidate autophagic process, the development of new therapeutic interventions requires a deeper understanding of the mechanisms that may lead to autophagy defects in PD and should take into account the multifactorial nature of the disease as well as the phenotypic heterogeneity of PD patients.
自噬是一种重要的分解代谢机制，它将错误折叠的蛋白质和受损的细胞器递送至溶酶体进行降解。自噬途径包括巨自噬、伴侣介导的自噬和微自噬，每种途径都涉及不同的底物递送至溶酶体的机制。这些途径的缺陷以及由此导致的蛋白聚集体的积累，代表了阿尔茨海默病、帕金森病和亨廷顿病等神经退行性疾病的共同病理生物学特征。本文通过总结最相关的遗传和实验证据，概述了自噬在帕金森病（PD）中的作用，说明了这一过程如何有助于疾病的发病机制。鉴于溶酶体参与自噬过程的最后一步，还将讨论溶酶体缺陷在自噬损伤中的作用及其对疾病的影响。本文还将简要介绍非神经元自噬在 PD 发病机制中的作用。此外，我们将研究新的药理学靶点和治疗策略，通过增强自噬，这些策略可能在理论上对 PD 有益。我们将特别关注天然产物，如酚类化合物，由于它们具有与低毒性相关的潜在功效，因此受到越来越多的关注。尽管人们已经做出了许多努力来阐明自噬过程，但新的治疗干预措施的开发需要更深入地了解可能导致 PD 中自噬缺陷的机制，并应考虑到疾病的多因素性质以及 PD 患者的表型异质性。
