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

Serena Venezia,Walter A Kaufmann,Gregor K Wenning,Nadia Stefanova

doi:10.1016/j.parkreldis.2021.09.007

Serena Venezia, Walter A Kaufmann + Show 2 more

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https://doi.org/10.1016/j.parkreldis.2021.09.007

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Journal: Parkinsonism and Related Disorders	Publication Date: Sep 11, 2021
Citations: 13	License type: cc-by

Affiliation: Universität Innsbruck

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.

Highlights

Toll-like receptor 4 (TLR4) is a member of a family of highly conserved molecules that recognize pathogen-associated molecular patterns, including exogenous and endogenous ligands, and modulate the innate immunity response
We showed previously that TLR4 deficiency interferes with the clearance of extracellular α-synuclein by microglia [6,7]
CD68 is a lysosomal marker of macrophages/microglia and we here sought to identify whether TLR4 deficiency may result in changes in the expres sion of CD68-positive microglia after inoculation of hu-αS PFFs

Summary

Introduction

Toll-like receptor 4 (TLR4) is a member of a family of highly conserved molecules that recognize pathogen-associated molecular patterns, including exogenous and endogenous ligands, and modulate the innate immunity response. TLR4 signaling was implicated in the proinflammatory response of microglia in toxin models of PD [8,9,10] as well as in in vitro exposure of microglial cells to α-synuclein [7,11]. These controversial sides of TLR4 action led to the question whether this innate immunity receptor is detrimental in α-synucleinopathy and whether it may serve as a target for disease modification. This finding was further corroborated in mice with oligodendroglial over expression of human α-synuclein treated with monophosphoryl lipid A, a non-toxic TLR4 agonist, which showed motor improvement, rescue of nigral and striatal neurons and region-specific reduction of the density of oligodendroglial α-synuclein cytoplasmic inclusions in the absence of a marked systemic inflammatory response [12]

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