Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037.
Infectious & Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
J Neurosci. 2022 Apr 6;42(14):3011-3024. doi: 10.1523/JNEUROSCI.1508-21.2022. Epub 2022 Feb 15.
Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins, such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown. Here, we used cell-based models, including human induced pluripotent stem cell-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathologic pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular buildup of misfolded proteins, with consequent secretion resulting in cell-to-cell spread. Thus, our data show that pathologic protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of individual neurons, but also for α-syn release and spread of disease throughout the nervous system. In Parkinson's disease and Lewy body dementia, dysfunctional autophagy contributes to accumulation and spread of aggregated α-synuclein. Here, we provide evidence that protein S-nitrosylation of p62 inhibits autophagic flux, contributing to α-synuclein aggregation and spread.
自噬途径的失调导致许多神经退行性疾病（包括帕金森病（PD）和路易体痴呆（LBD））中异常蛋白和受损细胞器的积累。自噬相关功能障碍也可能触发错误折叠蛋白（如α-突触核蛋白（α-syn））的分泌和扩散，α-syn 是 PD/LBD 中主要的错误折叠蛋白。然而，这些现象的机制在很大程度上仍然未知。在这里，我们使用了基于细胞的模型，包括人类诱导多能干细胞衍生的神经元、CRISPR/Cas9 技术和雄性转基因 PD/LBD 小鼠，以及对人类死后大脑（男性和女性）的验证。我们提供了对这种病理途径的机制见解。我们发现，自噬衔接蛋白 p62 的异常 S-亚硝基化导致自噬通量的抑制和错误折叠蛋白在细胞内的积累，随后导致分泌，从而导致细胞间传播。因此，我们的数据表明，病理性蛋白 p62 的 S-亚硝基化不仅是自噬抑制和个体神经元死亡的关键因素，也是 α-syn 释放和整个神经系统疾病传播的关键因素。在帕金森病和路易体痴呆中，自噬功能障碍导致聚集的α-突触核蛋白的积累和扩散。在这里，我们提供了证据表明 p62 的蛋白 S-亚硝基化抑制自噬通量，导致 α-synuclein 聚集和扩散。
