TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

Abstract Parkinson’s disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progres...

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Autores principales:	Anastazja M. Gorecki, Chidozie C. Anyaegbu, Ryan S. Anderton
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Parkinson’s disease TLR2 TLR4 α-Synuclein Gut-brain axis Gut barrier Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/54ceec2a5fac415c9066fd40889d3279
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spelling	oai:doaj.org-article:54ceec2a5fac415c9066fd40889d32792021-11-28T12:28:58ZTLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut10.1186/s40035-021-00271-02047-9158https://doaj.org/article/54ceec2a5fac415c9066fd40889d32792021-11-01T00:00:00Zhttps://doi.org/10.1186/s40035-021-00271-0https://doaj.org/toc/2047-9158Abstract Parkinson’s disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD, especially in a subset of people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations of gut homeostasis are hypothesized to contribute to α-synuclein aggregation in enteric neurons, which may spread to the brain over decades and eventually result in the characteristic central nervous system manifestations of PD, including neurodegeneration and motor impairments. However, the mechanisms linking gut disturbances and α-synuclein aggregation are still unclear. A plethora of research indicates that toll-like receptors (TLRs), especially TLR2 and TLR4, are critical mediators of gut homeostasis. Alongside their established role in innate immunity throughout the body, studies are increasingly demonstrating that TLR2 and TLR4 signalling shapes the development and function of the gut and the enteric nervous system. Notably, TLR2 and TLR4 are dysregulated in patients with PD, and may thus be central to early gut dysfunction in PD. To better understand the putative contribution of intestinal TLR2 and TLR4 dysfunction to early α-synuclein aggregation and PD, we critically discuss the role of TLR2 and TLR4 in normal gut function as well as evidence for altered TLR2 and TLR4 signalling in PD, by reviewing clinical, animal model and in vitro research. Growing evidence on the immunological aetiology of α-synuclein aggregation is also discussed, with a focus on the interactions of α-synuclein with TLR2 and TLR4. We propose a conceptual model of PD pathogenesis in which microbial dysbiosis alters the permeability of the intestinal barrier as well as TLR2 and TLR4 signalling, ultimately leading to a positive feedback loop of chronic gut dysfunction promoting α-synuclein aggregation in enteric and vagal neurons. In turn, α-synuclein aggregates may then migrate to the brain via peripheral nerves, such as the vagal nerve, to contribute to neuroinflammation and neurodegeneration typically associated with PD.Anastazja M. GoreckiChidozie C. AnyaegbuRyan S. AndertonBMCarticleParkinson’s diseaseTLR2TLR4α-SynucleinGut-brain axisGut barrierNeurology. Diseases of the nervous systemRC346-429ENTranslational Neurodegeneration, Vol 10, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Parkinson’s disease TLR2 TLR4 α-Synuclein Gut-brain axis Gut barrier Neurology. Diseases of the nervous system RC346-429
spellingShingle	Parkinson’s disease TLR2 TLR4 α-Synuclein Gut-brain axis Gut barrier Neurology. Diseases of the nervous system RC346-429 Anastazja M. Gorecki Chidozie C. Anyaegbu Ryan S. Anderton TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut
description	Abstract Parkinson’s disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD, especially in a subset of people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations of gut homeostasis are hypothesized to contribute to α-synuclein aggregation in enteric neurons, which may spread to the brain over decades and eventually result in the characteristic central nervous system manifestations of PD, including neurodegeneration and motor impairments. However, the mechanisms linking gut disturbances and α-synuclein aggregation are still unclear. A plethora of research indicates that toll-like receptors (TLRs), especially TLR2 and TLR4, are critical mediators of gut homeostasis. Alongside their established role in innate immunity throughout the body, studies are increasingly demonstrating that TLR2 and TLR4 signalling shapes the development and function of the gut and the enteric nervous system. Notably, TLR2 and TLR4 are dysregulated in patients with PD, and may thus be central to early gut dysfunction in PD. To better understand the putative contribution of intestinal TLR2 and TLR4 dysfunction to early α-synuclein aggregation and PD, we critically discuss the role of TLR2 and TLR4 in normal gut function as well as evidence for altered TLR2 and TLR4 signalling in PD, by reviewing clinical, animal model and in vitro research. Growing evidence on the immunological aetiology of α-synuclein aggregation is also discussed, with a focus on the interactions of α-synuclein with TLR2 and TLR4. We propose a conceptual model of PD pathogenesis in which microbial dysbiosis alters the permeability of the intestinal barrier as well as TLR2 and TLR4 signalling, ultimately leading to a positive feedback loop of chronic gut dysfunction promoting α-synuclein aggregation in enteric and vagal neurons. In turn, α-synuclein aggregates may then migrate to the brain via peripheral nerves, such as the vagal nerve, to contribute to neuroinflammation and neurodegeneration typically associated with PD.
format	article
author	Anastazja M. Gorecki Chidozie C. Anyaegbu Ryan S. Anderton
author_facet	Anastazja M. Gorecki Chidozie C. Anyaegbu Ryan S. Anderton
author_sort	Anastazja M. Gorecki
title	TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut
title_short	TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut
title_full	TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut
title_fullStr	TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut
title_full_unstemmed	TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut
title_sort	tlr2 and tlr4 in parkinson’s disease pathogenesis: the environment takes a toll on the gut
publisher	BMC
publishDate	2021
url	https://doaj.org/article/54ceec2a5fac415c9066fd40889d3279
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TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

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