A small molecule toll-like receptor antagonist rescues α-synuclein fibril pathology

J Biol Chem. 2022 Aug;298(8):102260. doi: 10.1016/j.jbc.2022.102260. Epub 2022 Jul 13.

Abstract

The propagation and accumulation of pathological α-synuclein protein is thought to underlie the clinical symptoms of the neurodegenerative movement disorder Parkinson's disease (PD). Consequently, there is significant interest in identifying the mechanisms that contribute to α-synuclein pathology, as these may inform therapeutic targets for the treatment of PD. One protein that appears to contribute to α-synuclein pathology is the innate immune pathogen recognition receptor, toll-like receptor 2 (TLR2). TLR2 is expressed on neurons, and its activation results in the accumulation of α-synuclein protein; however, the precise mechanism by which TLR2 contributes to α-synuclein pathology is unclear. Herein we demonstrate using human cell models that neuronal TLR2 activation acutely impairs the autophagy lysosomal pathway and markedly potentiates α-synuclein pathology seeded with α-synuclein preformed fibrils. Moreover, α-synuclein pathology could be ameliorated with a novel small molecule TLR2 inhibitor, including in induced pluripotent stem cell-derived neurons from a patient with PD. These results provide further insight into how TLR2 activation may promote α-synuclein pathology in PD and support that TLR2 may be a potential therapeutic target for the treatment of PD.

Keywords: Parkinson’s disease; fibril; inhibitor; lysosome; synuclein; toll-like receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Neurodegenerative Diseases* / metabolism
  • Neurons / metabolism
  • Parkinson Disease* / metabolism
  • Toll-Like Receptor 2 / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism

Substances

  • Toll-Like Receptor 2
  • alpha-Synuclein