α‐synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson’s disease
Open accessAbstract
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.
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Misfolded proteins and protein aggregates, including tau, Aβ, α-synuclein, mutant huntingtin, TDP-43, SOD1, and FUS induce microglial activation and neuroinflammation.
“Numerous studies have reported that misfolded proteins and protein aggregates, including tau,136–139 Aβ,138,140 α-synuclein,141–144 mutant huntingtin,145 TDP-43,132,146 superoxide dismutase 1 (SOD1),147–149 and fused in sarcoma (FUS)150 induce microglial activation and neuroinflammation.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [144]
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- Authors
- Tu, H., Yuan, B., Hou, X., Zhang, X., Pei, C., Ma, Y., Yang, Y., Fan, Y., Qin, Z., Liu, C., & Hu, L.
- Affiliations
- Soochow University (CN)
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience Soochow University Suzhou Jiangsu China
- Department of Neurology and Clinical Research Center of Neurological Disease The Second Affiliated Hospital of Soochow University Suzhou Jiangsu China
- Nanjing Medical University (CN)
- Corresponding author
- Hu, Li‐Fang
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2021-11-22
- Volume
- 20
- Issue
- 12
- Pages
- e13522-e13522
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC8672776
- OpenAlex
- W3217207941
- Cited by
- 152
- References
- 45
- Citations by year
- 2026: 26 · 2025: 36 · 2024: 42 · 2023: 26 · 2022: 22
- FWCI
- 10.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81571233, 81870997, 82171251)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- alpha-synuclein, Parkinson's disease, neuroinflammation, neurodegeneration, TLR4, p38 MAPK signaling, Akt/mTOR signaling, ATG5, dopaminergic neuron loss, substantia nigra, locomotor deficits
- MeSH terms
- Neuroinflammatory Diseases, Animals, Autophagy, Disease Models, Animal, Parkinson Disease, Mice, alpha-Synuclein
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