Microglia Process α-Synuclein Fibrils and Enhance their Pathogenicity in a TREM2-Dependent Manner
Min Xiong1, Danhao Xia1, Honglu Yu1
1Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Abstract:
Parkinson's disease (PD) is characterized by the deposition of misfolded α-synuclein (α-syn) in the brain. Converging evidence indicates that the intracellular transmission and subsequent templated amplification of α-syn are involved in the onset and progression of PD. However, the molecular mechanisms underlying the cell-to-cell transmission of pathological α-syn remain poorly understood. Microglia is highly activated in the brains of PD patients. Here, it is shown that depletion of microglia slows the spread of pathological α-syn pathology in mice injected with α-syn fibrils. Microglia phagocytose α-syn fibrils and transform them into more toxic species. The phagocytosis of α-syn fibrils by microglia is partially mediated by triggering a receptor expressed on myeloid cells 2 (TREM2), a transmembrane protein expressed on the surface of microglia. The endocytosed α-syn fibrils are then cleaved by the lysosomal proteinase asparagine endopeptidase (AEP) to generate truncated α-syn 1-103 fibrils with enhanced seeding activity. Knockout of TREM2 and AEP impedes the endocytosis and cleavage of α-syn fibrils, respectively. The results demonstrate that TREM2-mediated phagocytosis of α-syn fibrils by microglia and subsequent AEP-mediated cleavage of α-syn fibrils contribute to the spread of α-syn in the brain. Blocking either of these two steps attenuates the progression of α-syn pathology.
Insights
Microglia play a key role in Parkinson's disease (PD) progression by phagocytosing and transforming alpha-synuclein (α-syn) fibrils. Targeting TREM2-mediated uptake and AEP cleavage by microglia can slow the spread of this toxic protein.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Parkinson's disease (PD) involves misfolded alpha-synuclein (α-syn) aggregation and cell-to-cell transmission.
- Microglia, the brain's immune cells, are activated in PD patients, suggesting a role in disease progression.
- Mechanisms of pathological α-syn cell-to-cell spread remain incompletely understood.
Purpose of the Study:
- To investigate the role of microglia in the cell-to-cell transmission of pathological α-syn.
- To elucidate the molecular mechanisms by which microglia contribute to α-syn spread in PD.
- To identify potential therapeutic targets for blocking α-syn pathology propagation.
Main Methods:
- Utilized mouse models injected with α-syn fibrils.
- Depleted microglia to assess their impact on α-syn pathology spread.
- Investigated the role of triggering receptor expressed on myeloid cells 2 (TREM2) and asparagine endopeptidase (AEP) in microglia-mediated α-syn processing.
- Examined the effects of TREM2 and AEP knockout on α-syn endocytosis and cleavage.
Main Results:
- Microglia phagocytose α-syn fibrils, generating more toxic species.
- TREM2 mediates the phagocytosis of α-syn fibrils by microglia.
- Asparagine endopeptidase (AEP) cleaves endocytosed α-syn fibrils into truncated forms with enhanced seeding activity.
- Depletion of microglia, knockout of TREM2, or knockout of AEP significantly slowed the spread of α-syn pathology.
Conclusions:
- Microglia actively contribute to the spread of pathological α-syn in the brain.
- TREM2-mediated phagocytosis and subsequent AEP-mediated cleavage are critical steps in microglia's role in α-syn propagation.
- Targeting TREM2-dependent phagocytosis or AEP-mediated cleavage represents a potential therapeutic strategy to attenuate Parkinson's disease progression.
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