A breakdown in microglial metabolic reprogramming causes internalization dysfunction of α-synuclein in a mouse model of Parkinson's disease

Background: The alpha-synuclein released by neurons activates microglia, which then engulfs alpha-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 ofTRPV1 in microglial autophagy. alpha-synuclein preformed fibril (PFF)TRPV1(flox/flox)Cx3cr1(Cre) mouse model of sporadic PD were employed to study the capacity ofTRPV1 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-1 alpha 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-1 alpha pathway. Capsaicin attenuated phosphorylation of alpha-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 TRPV1(flox/)(flox), Cx3cr1(Cre) 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 TRPV1(flox/)(flox); Cx3cr1(Cre) mice. Conclusion: The findings suggest that modulating microglial metabolism might be a new therapeutic strategy for PD.

Automated summary

The study suggests that modulating microglial metabolism and activating TRPV1 channels may be a promising therapeutic strategy for Parkinson's disease, as they can improve energy metabolism and attenuate neurodegeneration.