α-突触核蛋白内化功能障碍导致帕金森病小鼠模型中小胶质细胞代谢重编程的崩溃。
A breakdown in microglial metabolic reprogramming causes internalization dysfunction of α-synuclein in a mouse model of Parkinson's disease.
机构信息
Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
出版信息
J Neuroinflammation. 2022 May 22;19(1):113. doi: 10.1186/s12974-022-02484-0.
BACKGROUND
The α-synuclein released by neurons activates microglia, which then engulfs α-synuclein for degradation via autophagy. Reactive microglia are a major pathological feature of Parkinson's disease (PD), although the exact role of microglia in the pathogenesis of PD remains unclear. Transient receptor potential vanilloid type 1 (TRPV1) channels are nonselective cation channel protein that have been proposed as neuroprotective targets in neurodegenerative diseases.
METHODS
Using metabolic profiling, microglia energy metabolism was measured including oxidative phosphorylation and aerobic glycolysis. The mRFP-GFP-tagged LC3 reporter was introduced to characterize the role of TRPV1 in microglial autophagy. α-synuclein preformed fibril (PFF) TRPV1; Cx3cr1 mouse model of sporadic PD were employed to study the capacity of TRPV1 activation to attenuate neurodegeneration process.
RESULTS
We found that acute exposure to PFF caused microglial activation as a result of metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis via the AKT-mTOR-HIF-1α pathway. Activated microglia eventually reached a state of chronic PFF-tolerance, accompanied by broad defects in energy metabolism. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued metabolic impairments in PFF-tolerant microglia and also defects in mitophagy caused by disruption of the AKT-mTOR-HIF-1α pathway. Capsaicin attenuated phosphorylation of α-synuclein in primary neurons by boosting phagocytosis in PFF-tolerant microglia in vitro. Finally, we found that behavioral deficits and loss of dopaminergic neurons were accelerated in the PFF TRPV1; Cx3cr1 mouse model of sporadic PD. We identified defects in energy metabolism, mitophagy and phagocytosis of PFF in microglia from the substantia nigra pars compacta of TRPV1; Cx3cr1 mice.
CONCLUSION
The findings suggest that modulating microglial metabolism might be a new therapeutic strategy for PD.
背景
神经元释放的α-突触核蛋白激活小胶质细胞，小胶质细胞通过自噬吞噬α-突触核蛋白进行降解。活性小胶质细胞是帕金森病（PD）的主要病理学特征，尽管小胶质细胞在 PD 发病机制中的确切作用仍不清楚。瞬时受体电位香草酸型 1（TRPV1）通道是非选择性阳离子通道蛋白，已被提议作为神经退行性疾病的神经保护靶点。
方法
使用代谢谱分析，测量包括氧化磷酸化和有氧糖酵解在内的小胶质细胞能量代谢。引入 mRFP-GFP 标记的 LC3 报告基因，以表征 TRPV1 在小胶质细胞自噬中的作用。使用 α-突触核蛋白原纤维形成（PFF）TRPV1；Cx3cr1 散发性 PD 小鼠模型研究 TRPV1 激活减轻神经退行性过程的能力。
结果
我们发现，急性暴露于 PFF 会导致小胶质细胞激活，这是通过 AKT-mTOR-HIF-1α 途径从氧化磷酸化到有氧糖酵解的代谢重编程的结果。激活的小胶质细胞最终达到慢性 PFF 耐受状态，同时伴有广泛的能量代谢缺陷。我们表明，用 TRPV1 激动剂辣椒素治疗可挽救 PFF 耐受小胶质细胞的代谢损伤，并可挽救 AKT-mTOR-HIF-1α 途径破坏引起的线粒体自噬缺陷。辣椒素通过在体外增强 PFF 耐受小胶质细胞的吞噬作用来减弱原代神经元中α-突触核蛋白的磷酸化。最后，我们发现 PFF TRPV1；Cx3cr1 散发性 PD 小鼠模型中的行为缺陷和多巴胺能神经元丢失加速。我们从 TRPV1；Cx3cr1 小鼠黑质致密部的小胶质细胞中发现了 PFF 能量代谢、线粒体自噬和吞噬作用的缺陷。
结论
研究结果表明，调节小胶质细胞代谢可能是 PD 的一种新的治疗策略。
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