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Updated: Jan 9, 2026
Analyzing the Parkinson's Disease Mouse Model Induced by Adeno-associated Viral Vectors Encoding Human α-Synuclein
Published on: July 29, 2022
Neuronal alpha-synuclein-mediated autophagy drives lipid droplets accumulation in astrocytes and microglia and
Wenqiang Xin1, Wei Wei2, Xiaoyue Luo3
1Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
Background:
Lipid droplets (LDs) agglomeration in glial cells after stroke contributes to cellular dysfunction and neuronal injury. Alpha-synuclein has been identified as a critical regulator in the uptake and metabolism of fatty acids across various neurological disorders. Moreover, alterations in autophagic function can impact the agglomeration of LDs following a stroke. It is also well-established that alpha-synuclein is directly involved in neuronal autophagy. Although substantial research has been conducted on the relationship between alpha-synuclein and lipid metabolism, the precise mechanisms by which alpha-synuclein modulates lipid metabolism in glial cells post-stroke are not yet fully understood.
Methods:
Primary neurons and glial cells from neonatal mice were used to establish in vitro oxygen-glucose deprivation/reoxygenation and neuron-glia co-culture models. In vivo studies employed alpha-synuclein knockdown mice subjected to middle cerebral artery occlusion. Analysis of readout parameters using various techniques, including qRT-PCR, immunofluorescence, western blot assays, phagocytosis and behavioral tests. Utilizing both in vitro and in vivo stroke models, we investigated how alpha-synuclein modulates the interactions between neurons and microglia/astrocytes.
Results:
We found that ischemic stroke induces LD agglomeration, triggers autophagy, and increases alpha-synuclein levels. Knockdown of alpha-synuclein reduced LD formation, restored autophagic balance, and improved neurological outcomes. In co-culture, silencing neuronal alpha-synuclein or enhancing neuronal autophagy decreased LD accumulation and modified LD-associated protein expression in microglia and astrocytes. Moreover, neuronal alpha-synuclein and autophagy regulation modulated glial phagocytic activity without directly altering glial autophagy. Additionally, changes in LD accumulation appear to play a pivotal role in mediating interactions between glial cells and neurons, thereby influencing cell viability and autophagy. Consistent with these findings, treatment with alpha-synuclein siRNA alleviates stroke-induced neurological deficits.
Conclusion:
Alpha-synuclein regulates lipid metabolism and phagocytic activity in glial cells through autophagy mechanisms under ischemic conditions, providing new insight into therapeutic strategies for stroke.
