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MANF 通过激活自噬途径抑制 -Synuclein 积累。

MANF Inhibits -Synuclein Accumulation through Activation of Autophagic Pathways.

机构信息

Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China.

Biomedical Research Center, Tongji University Suzhou Institute, Jiangsu 215101, China.

出版信息

Oxid Med Cell Longev. 2022 Jul 8;2022:7925686. doi: 10.1155/2022/7925686. eCollection 2022.

DOI:10.1155/2022/7925686
PMID:35847585
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9286947/
Abstract

Progressive accumulation of misfolded SNCA/-synuclein is key to the pathology of Parkinson's disease (PD). Drugs aiming at degrading SNCA may be an efficient therapeutic strategy for PD. Our previous study showed that mesencephalic astrocyte-derived neurotrophic factor (MANF) facilitated the removal of misfolded SNCA and rescued dopaminergic (DA) neurons, but the underlying mechanisms remain unknown. In this study, we showed that AAV8-MANF relieved Parkinsonian behavior in rotenone-induced PD model and reduced SNCA accumulation in the substantia nigra. By establishing wildtype (WT) SNCA overexpression cellular model, we found that chaperone-mediated-autophagy (CMA) and macroautophagy were both participated in MANF-mediated degradation of SNCA. Nuclear factor erythroid 2-related factor (Nrf2) was activated to stimulating macroautophagy activity when CMA pathway was impaired. Using A53T mutant SNCA overexpression cellular model to mimic CMA dysfunction situation, we concluded that macroautophagy rather than CMA was responsible to the degradation of SNCA, and this degradation was mediated by Nrf2 activation. Hence, our findings suggested that MANF has potential therapeutic value for PD. Nrf2 and its role in MANF-mediated degradation may provide new sights that target degradation pathways to counteract SNCA pathology in PD.

摘要

错误折叠的 SNCA/-突触核蛋白的进行性积累是帕金森病 (PD) 病理学的关键。旨在降解 SNCA 的药物可能是 PD 的一种有效治疗策略。我们之前的研究表明，中脑星形胶质细胞衍生的神经营养因子 (MANF) 有助于清除错误折叠的 SNCA 并挽救多巴胺能 (DA) 神经元，但潜在机制尚不清楚。在这项研究中，我们表明 AAV8-MANF 缓解了鱼藤酮诱导的 PD 模型中的帕金森病行为，并减少了黑质中 SNCA 的积累。通过建立野生型 (WT) SNCA 过表达细胞模型，我们发现伴侣介导的自噬 (CMA) 和巨自噬都参与了 MANF 介导的 SNCA 降解。当 CMA 途径受损时，核因子红细胞 2 相关因子 (Nrf2) 被激活以刺激巨自噬活性。使用 A53T 突变 SNCA 过表达细胞模型模拟 CMA 功能障碍情况，我们得出结论，巨自噬而不是 CMA 负责 SNCA 的降解，并且这种降解是由 Nrf2 激活介导的。因此，我们的发现表明 MANF 对 PD 具有潜在的治疗价值。Nrf2 及其在 MANF 介导的降解中的作用可能为靶向降解途径以对抗 PD 中 SNCA 病理学提供新的视角。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4291/9286947/86d7a2c266ac/OMCL2022-7925686.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4291/9286947/e6edd00e3844/OMCL2022-7925686.002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4291/9286947/8acc34ad511d/OMCL2022-7925686.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4291/9286947/3317a72284c6/OMCL2022-7925686.008.jpg

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