| First Author | Tu HY | Year | 2021 |
| Journal | Aging Cell | Volume | 20 |
| Issue | 12 | Pages | e13522 |
| PubMed ID | 34811872 | Mgi Jnum | J:320252 |
| Mgi Id | MGI:6841049 | Doi | 10.1111/acel.13522 |
| Citation | Tu HY, et al. (2021) alpha-synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson's disease. Aging Cell 20(12):e13522 |
| abstractText | The cell-to-cell transfer of alpha-synuclein (alpha-Syn) greatly contributes to Parkinson's disease (PD) pathogenesis and underlies the spread of alpha-Syn pathology. During this process, extracellular alpha-Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular alpha-Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular alpha-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 alpha-Syn-overexpressing mice induced by adeno-associated virus (AAV2/9)-encoded wildtype human alpha-Syn injection into the substantia nigra (SN). Mechanistically, alpha-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 alpha-Syn-induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by alpha-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 alpha-Syn-overexpressing mice. Taken together, the results suggest that extracellular alpha-Syn, via Tlr4-dependent p38 and Akt-mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development. |
