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Updated: Sep 22, 2025
Analyzing the Parkinson's Disease Mouse Model Induced by Adeno-associated Viral Vectors Encoding Human α-Synuclein
Published on: July 29, 2022
A breakdown in microglial metabolic reprogramming causes internalization dysfunction of α-synuclein in a mouse model
Jia Lu1, Chenfei Wang1, Xin Cheng2
1Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
Background:
The α-synuclein released by neurons activates microglia, which then engulfs α-synuclein for degradation via autophagy. Reactive microglia are a major pathological feature of Parkinson's disease (PD), although the exact role of microglia in the pathogenesis of PD remains unclear. Transient receptor potential vanilloid type 1 (TRPV1) channels are nonselective cation channel protein that have been proposed as neuroprotective targets in neurodegenerative diseases.
Methods:
Using metabolic profiling, microglia energy metabolism was measured including oxidative phosphorylation and aerobic glycolysis. The mRFP-GFP-tagged LC3 reporter was introduced to characterize the role of TRPV1 in microglial autophagy. α-synuclein preformed fibril (PFF) TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD were employed to study the capacity of TRPV1 activation to attenuate neurodegeneration process.
Results:
We found that acute exposure to PFF caused microglial activation as a result of metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis via the AKT-mTOR-HIF-1α pathway. Activated microglia eventually reached a state of chronic PFF-tolerance, accompanied by broad defects in energy metabolism. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued metabolic impairments in PFF-tolerant microglia and also defects in mitophagy caused by disruption of the AKT-mTOR-HIF-1α pathway. Capsaicin attenuated phosphorylation of α-synuclein in primary neurons by boosting phagocytosis in PFF-tolerant microglia in vitro. Finally, we found that behavioral deficits and loss of dopaminergic neurons were accelerated in the PFF TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD. We identified defects in energy metabolism, mitophagy and phagocytosis of PFF in microglia from the substantia nigra pars compacta of TRPV1flox/flox; Cx3cr1Cre mice.
Conclusion:
The findings suggest that modulating microglial metabolism might be a new therapeutic strategy for PD.
Insights
Targeting microglial metabolism shows promise for Parkinson's disease (PD). Activating Transient Receptor Potential Vanilloid type 1 (TRPV1) channels with capsaicin improved energy metabolism and neuroprotection in a PD mouse model.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Microglia activation by alpha-synuclein is a hallmark of Parkinson's disease (PD).
- The precise role of microglia in PD pathogenesis is unclear.
- Transient Receptor Potential Vanilloid type 1 (TRPV1) channels are explored as neuroprotective targets.
Purpose of the Study:
- To investigate the role of TRPV1 in microglial energy metabolism and autophagy in PD.
- To determine if TRPV1 activation can mitigate neurodegeneration in a mouse model of sporadic PD.
Main Methods:
- Metabolic profiling of microglia, including oxidative phosphorylation and aerobic glycolysis.
- Utilized a reporter system to assess microglial autophagy.
- Employed a TRPV1 conditional knockout mouse model with alpha-synuclein preformed fibrils (PFF) to study PD.
Main Results:
- PFF exposure induced microglial metabolic reprogramming towards aerobic glycolysis via the AKT-mTOR-HIF-1α pathway.
- Chronic PFF exposure led to metabolic defects and impaired mitophagy in microglia.
- TRPV1 agonist capsaicin treatment rescued metabolic impairments and enhanced phagocytosis in PFF-exposed microglia.
- TRPV1 deficiency exacerbated behavioral deficits and dopaminergic neuron loss in the PD mouse model.
Conclusions:
- Microglial metabolic reprogramming is a key feature in PD pathogenesis.
- Modulating microglial metabolism via TRPV1 activation offers a potential therapeutic strategy for PD.
- Targeting microglial energy metabolism and autophagy presents a novel therapeutic avenue for Parkinson's disease.
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