Toll-like receptor 4 deficiency facilitates α-synuclein propagation and neurodegeneration in a mouse model of prodromal Parkinson's disease

Parkinsonism Relat Disord. 2021 Oct;91:59-65. doi: 10.1016/j.parkreldis.2021.09.007. Epub 2021 Sep 11.

Abstract

The evidence linking innate immunity mechanisms and neurodegenerative diseases is growing, but the specific mechanisms are incompletely understood. Experimental data suggest that microglial TLR4 mediates the uptake and clearance of α-synuclein also termed synucleinophagy. The accumulation of misfolded α-synuclein throughout the brain is central to Parkinson's disease (PD). The distribution and progression of the pathology is often attributed to the propagation of α-synuclein. Here, we apply a classical α-synuclein propagation model of prodromal PD in wild type and TLR4 deficient mice to study the role of TLR4 in the progression of the disease. Our data suggest that TLR4 deficiency facilitates the α-synuclein seed spreading associated with reduced lysosomal activity of microglia. Three months after seed inoculation, more pronounced proteinase K-resistant α-synuclein inclusion pathology is observed in mice with TLR4 deficiency. The facilitated propagation of α-synuclein is associated with early loss of dopamine transporter (DAT) signal in the striatum and loss of dopaminergic neurons in substantia nigra pars compacta of TLR4 deficient mice. These new results support TLR4 signaling as a putative target for disease modification to slow the progression of PD and related disorders.

Keywords: CD68; DAT; Disease progression; Microglia; Parkinson's disease; Synuclein; TLR4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Corpus Striatum / metabolism
  • Disease Models, Animal
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopaminergic Neurons / metabolism
  • Lysosomes / metabolism
  • Mice
  • Microglia / metabolism
  • Nerve Degeneration / genetics*
  • Parkinson Disease / genetics*
  • Pars Compacta / metabolism
  • Signal Transduction / genetics*
  • Toll-Like Receptor 4 / deficiency*
  • alpha-Synuclein / metabolism*

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Toll-Like Receptor 4
  • alpha-Synuclein