α‐synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson’s disease |
| |
Authors: | HaiYue Tu BaoShi Yuan XiaoOu Hou XiaoJun Zhang ChongShuang Pei YaTing Ma YaPing Yang Yi Fan ZhengHong Qin ChunFeng Liu LiFang Hu |
| |
Institution: | 1. Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou Jiangsu, China ; 2. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou Jiangsu, China ; 3. Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou Jiangsu, China ; 4. Department of Pharmacology, Nanjing Medical University, Nanjing Jiangsu, China |
| |
Abstract: | The cell‐to‐cell transfer of α‐synuclein (α‐Syn) greatly contributes to Parkinson''s disease (PD) pathogenesis and underlies the spread of α‐Syn pathology. During this process, extracellular α‐Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α‐Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α‐Syn inhibited the autophagy initiation, as indicated by LC3‐II reduction and p62 protein elevation in BV2 and cultured primary microglia. The in vitro findings were verified in microglia‐enriched population isolated from α‐Syn‐overexpressing mice induced by adeno‐associated virus (AAV2/9)‐encoded wildtype human α‐Syn injection into the substantia nigra (SN). Mechanistically, α‐Syn led to microglial autophagic impairment through activating toll‐like receptor 4 (Tlr4) and its downstream p38 and Akt‐mTOR signaling because Tlr4 knockout and inhibition of p38, Akt as well as mTOR prevented α‐Syn‐induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by α‐Syn. Functionally, the in vivo evidence showed that lysozyme 2 Cre (Lyz2 cre)‐mediated depletion of autophagy‐related gene 5 (Atg5) in microglia aggravated the neuroinflammation and dopaminergic neuron losses in the SN and exacerbated the locomotor deficit in α‐Syn‐overexpressing mice. Taken together, the results suggest that extracellular α‐Syn, via Tlr4‐dependent p38 and Akt‐mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development. |
| |
Keywords: | autophagy microglia neuroinflammation Parkinson''s disease α ‐ synuclein |
|
|