Heat Shock Protein 90 in Parkinson’s Disease: Profile of a Serial Killer

神经保护 帕金 蛋白质稳态 黑质 热休克蛋白 HDAC6型 热休克蛋白90 帕金森病 生物 神经退行性变 自噬 多巴胺能 LRRK2 品脱1 神经科学 程序性细胞死亡 氧化应激 细胞生物学 组蛋白脱乙酰基酶 医学 疾病 多巴胺 细胞凋亡 生物化学 内科学 组蛋白 基因
作者
Heba M. Mansour,Ahmed F. Mohamed,Mahmoud M. Khattab,Aiman S. El‐Khatib
出处
期刊:Neuroscience [Elsevier]
卷期号:537: 32-46
标识
DOI:10.1016/j.neuroscience.2023.11.031
摘要

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by abnormal α-synuclein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, as well as progressive death of dopaminergic neurons in the substantia nigra. Molecular chaperones play a role in stabilizing proteins and helping them achieve their proper structure. Previous studies have shown that overexpression of heat shock protein 90 (HSP90) can lead to the death of dopaminergic neurons associated with PD. Inhibiting HSP90 is considered a potential treatment approach for neurodegenerative disorders, as it may reduce protein aggregation and related toxicity, as well as suppress various forms of regulated cell death (RCD). This review provides an overview of HSP90 and its role in PD, focusing on its modulation of proteostasis and quality control of LRRK2. The review also explores the effects of HSP90 on different types of RCD, such as apoptosis, chaperone-mediated autophagy (CMA), necroptosis, and ferroptosis. Additionally, it discusses HSP90 inhibitors that have been tested in PD models. We will highlight the under-investigated neuroprotective effects of HSP90 inhibition, including modulation of oxidative stress, mitochondrial dysfunction, PINK/PARKIN, heat shock factor 1 (HSF1), histone deacetylase 6 (HDAC6), and the PHD2-HSP90 complex-mediated mitochondrial stress pathway. By examining previous literature, this review uncovers overlooked neuroprotective mechanisms and emphasizes the need for further research on HSP90 inhibitors as potential therapeutic strategies for PD. Finally, the review discusses the potential limitations and possibilities of using HSP90 inhibitors in PD therapy.
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