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

J Neuroinflammation. 2022 May 22;19(1):113. doi: 10.1186/s12974-022-02484-0.

Abstract

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.

Keywords: Autophagy; Capsaicin; Microglia; TRPV1; α-Synuclein.

MeSH terms

  • Animals
  • Capsaicin
  • Disease Models, Animal
  • Dopaminergic Neurons / pathology
  • Mice
  • Microglia* / metabolism
  • Parkinson Disease* / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • TRPV Cation Channels* / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism

Substances

  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • alpha-Synuclein
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Capsaicin