VPS35 Regulates Microglial Lipid Droplet Accumulation in Parkinson's Disease via Rab7
Yue Liang1, Tong Chang1, Leping Yan1
1Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
Abstract:
Microglial dysfunction and aberrant lipid metabolism are emerging as key contributors to Parkinson's disease (PD) pathogenesis. However, the specific role and regulation of lipid droplets (LDs) within microglia remain poorly defined. In this study, we employed MPTP- and LPS-induced PD mouse models and an in vitro system utilizing astrocyte-conditioned medium to model disease-relevant lipid stress and found enhanced LD accumulation in microglia. VPS35 expression was decreased in microglia, correlating with elevated microglial LD levels in PD mouse models. We then performed genetic manipulations (knockdown and overexpression) of VPS35, including the PD-associated D620N mutant, in primary microglia and assessed LD accumulation, phagocytic function, inflammatory responses, and integrated stress pathways. We showed that VPS35 knockdown exacerbated the accumulation of LDs in microglia. Conversely, VPS35 overexpression ameliorated LD formation, improved phagocytic function, and reduced inflammatory and integrated stress responses in microglia. The PD-related VPS35[D620N] mutation abolished these protective effects. We further found that VPS35 interacts with Rab7 to maintain lysosomal function, and the D620N mutation disrupts this interaction, leading to defective LD clearance. Our findings reveal VPS35 dysfunction as a key pathogenic mechanism in PD, where the D620N mutation disrupts microglial lipid handling to promote disease progression, thereby nominating VPS35 restoration as a promising therapeutic strategy.
Insights
VPS35 protein dysfunction impairs microglial lipid metabolism, worsening Parkinson's disease (PD). Restoring VPS35 function may offer a novel therapeutic strategy for PD by improving microglial lipid handling.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Microglial dysfunction and altered lipid metabolism are implicated in Parkinson's disease (PD) pathogenesis.
- The precise role and regulation of lipid droplets (LDs) in microglia during PD are not well understood.
Purpose of the Study:
- To investigate the role of VPS35 in microglial lipid droplet accumulation and function in Parkinson's disease.
- To determine the impact of VPS35 genetic manipulation and the PD-associated D620N mutation on microglial responses.
Main Methods:
- Utilized MPTP- and LPS-induced PD mouse models and in vitro systems with astrocyte-conditioned medium.
- Performed genetic knockdown and overexpression of VPS35, including the D620N mutant, in primary microglia.
- Assessed LD accumulation, phagocytic capacity, inflammatory markers, and integrated stress pathways.
Main Results:
- Microglia showed increased LD accumulation in PD models, correlating with decreased VPS35 expression.
- VPS35 knockdown worsened LD accumulation, while overexpression ameliorated it, improving phagocytosis and reducing inflammation.
- The PD-associated VPS35[D620N] mutation negated these protective effects and disrupted lysosomal function via impaired Rab7 interaction, hindering LD clearance.
Conclusions:
- VPS35 dysfunction, particularly the D620N mutation, is a key pathogenic mechanism in PD, disrupting microglial lipid metabolism and promoting disease progression.
- Targeting VPS35 offers a potential therapeutic avenue for Parkinson's disease by restoring normal microglial lipid handling and function.
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