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

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) TRPV1(flox/flox); Cx3cr1(Cre) 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 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02484-0.