HSPA9的下调减少了小鼠黑质中酪氨酸羟酶阳性神经元并诱导帕金森病样运动损伤。

IF 3.2 2区 生物学 Q3 CELL BIOLOGY
Animal Cells and Systems Pub Date : 2025-10-14 eCollection Date: 2025-01-01 DOI:10.1080/19768354.2025.2569875
Hyejin Hyung, Soyoung Jang, Si-Yong Kim, Ji-Eun Bae, Ji Yeong Park, Su-Geun Lim, Jiwon Ko, Soyeon Jang, Joon Bum Kim, Hee Young Chae, Song Park, Junkoo Yi, Dong Kyu Choi, Myoung Ok Kim, Hyun-Shik Lee, Dong-Hyung Cho, Zae Young Ryoo
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引用次数: 0

摘要

帕金森病(PD)是一种进行性神经系统疾病,以中脑多巴胺能神经元变性和致残性运动损伤为特征。热休克蛋白家族A成员9 (HSPA9)通过调节各种线粒体蛋白的输入,在神经元稳态中起着至关重要的作用。HSPA9在阿尔茨海默病和帕金森病等神经退行性疾病中下调,其缺失导致线粒体过度断裂并伴有氧化应激,从而导致多巴胺能神经元损伤。此外,HSPA9与多种PD相关蛋白相互作用,包括Pink1、DJ-1和α-synuclein,但HSPA9在PD病理生理中的确切作用尚不清楚。为了进一步探索HSPA9在PD发病机制中的作用,我们建立了HSPA9基因敲除小鼠。Hspa9的单倍不足(Hspa9 +/-)与纹状体和黑质中酪氨酸羟化酶阳性神经元的缺失有关。此外,Hspa9单倍不足诱导线粒体过度分裂,增强凋亡信号,并导致旋转棒试验中运动性能下降。在Hspa9 +/-小鼠中给予线粒体神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)进一步加剧了多巴胺能神经元的丢失,加重了运动损伤,并增强了凋亡效应物caspase-3的激活。这些结果提示HSPA9的下调可能参与PD的发生和进展,可能为PD的治疗提供新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Down-regulation of HSPA9 reduces tyrosine hydroxylase-positive neurons in mouse substantia nigra and induces Parkinson's disease-like motor impairments.

Parkinson's disease (PD) is a progressive neurological disorder characterized by the degeneration of midbrain dopaminergic neurons and disabling motor impairments. Heat shock protein family A member 9 (HSPA9) play a crucial role in neuronal homeostasis by regulating the import of various mitochondrial proteins. HSPA9 is down-regulated in neurodegenerative diseases such as Alzheimer's disease and PD, and its loss leads to excessive mitochondrial fragmentation with oxidative stress, which subsequently causes damage to dopaminergic neurons. Moreover, HSPA9 interacts with multiple PD-associated proteins, including Pink1, DJ-1, and α-synuclein, however precise roles of HSPA9 in PD pathophysiology remain unclear. To further explore the contributions of HSPA9 in PD pathogenesis, we developed an HSPA9 knockout mouse. Haploinsufficiency of Hspa9 (Hspa9 +/-) was associated with the loss of tyrosine hydroxylase-positive neurons in the striatum and substantia nigra. Furthermore, Hspa9 haploinsufficiency induced excessive mitochondrial fission, enhanced apoptotic signaling, and resulted in diminished motor performance during the rotarod test. Administration of the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Hspa9 +/- mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.

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来源期刊
Animal Cells and Systems
Animal Cells and Systems 生物-动物学
CiteScore
4.50
自引率
24.10%
发文量
33
审稿时长
6 months
期刊介绍: Animal Cells and Systems is the official journal of the Korean Society for Integrative Biology. This international, peer-reviewed journal publishes original papers that cover diverse aspects of biological sciences including Bioinformatics and Systems Biology, Developmental Biology, Evolution and Systematic Biology, Population Biology, & Animal Behaviour, Molecular and Cellular Biology, Neurobiology and Immunology, and Translational Medicine.
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