Single Nucleotide Polymorphisms Associated With Gut Homeostasis Influence Risk and Age-at-Onset of Parkinson's Disease

Gorecki, Anastazja M.; Bakeberg, Megan C.; Theunissen, Frances; Kenna, Jade; Hoes, Madison E.; Pfaff, Abigail L; Akkari, P. Anthony; Dunlop, Sarah; Kõks, Sulev; Mastaglia, Frank; Anderton, Ryan S.

doi:10.3389/fnagi.2020.603849

Cited by 19 publications

(19 citation statements)

References 86 publications

(96 reference statements)

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“…In light of an established role in innate immunity, TLR2 likely plays a crucial part in microbial-induced inflammation throughout the whole body, and several lines of evidence demonstrate alterations of TLR2 signalling in people with PD. First, a C-to-T single nucleotide polymorphism in TLR2 rs3804099 is associated with increased PD risk in a Han Chinese population, especially among those with late-onset PD [ 44 ], whereas a recent study utilising a Caucasian subset of the Parkinson’s Progression Markers Initiative (PPMI) cohort reported that TC heterozygotes and minor CC homozygotes of TLR2 rs3804099 have significantly increased PD risk [ 45 ], indicating possible geographical or ethnic differences regulating the link between TLR2 polymorphisms and PD. This polymorphism is a significant expression quantitative trait loci (eQTL) in certain cell types, which is predicted to influence TLR2 mRNA levels [ 45 ] and is associated with susceptibility to bacterial infections [ 46 , 47 ], however further research is needed to confirm the direct effect of TLR2 rs3804099 on protein levels.…”

Section: Tlrsmentioning

confidence: 99%

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

Gorecki

Anyaegbu

Anderton

2021

Transl Neurodegener

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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.

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Section: Tlrsmentioning

confidence: 99%

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

Gorecki

Anyaegbu

Anderton

2021

Transl Neurodegener

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“…SCFAs like butyrate can regulate oxidative stress in the colonic mucosa by decreasing the reactive oxygen species which promotes the accumulation of α-synuclein in the ENS [ 166 ]. A study has presented the association between PD and SNPs in genes responsible for binding of bacterial metabolites and intestinal homeostasis, demonstrating that genetic variation in the bacterial receptor may modulate risk and age-of-onset in idiopathic PD [ 167 ].…”

Section: Intestinal Dysfunctions In Pdmentioning

confidence: 99%

Intestinal Inflammation and Parkinson’s Disease

Li¹,

Chen²,

Jiang³

et al. 2021

Aging and disease

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“…It was also shown that gut inflammation is a main pathological feature occurring in both PD and CD and this inflammation may contribute to α-synuclein aggregation ( Dzamko et al, 2017 ; Drobny et al, 2021 ). Additionally, some SNPs in genes responsible for binding bacterial metabolites and intestinal homeostasis were associated with PD ( Gorecki et al, 2020 ). All above suggested CD have a link with neurodegenerative diseases, in some respects of genetics and intestinal flora ( Voros et al, 2013 ; Cao et al, 2018 ; Spielman et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Association Analysis of WNT3, HLA-DRB5 and IL1R2 Polymorphisms in Chinese Patients With Parkinson’s Disease and Multiple System Atrophy

Hou

et al. 2021

Front. Genet.

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Background: The association between inflammation and neurodegeneration has long been observed in parkinson’s disease (PD) and multiple system atrophy (MSA). Previous genome-wide association studies (GWAS) and meta-analyses have identified several risk loci in inflammation-associated genes associated with PD.Objective: To investigate whether polymorphisms in some inflammation-associated genes could modulate the risk of developing PD and MSA in a Southwest Chinese population.Methods: A total of 2,706 Chinese subjects comprising 1340 PD, 483 MSA and 883 healthy controls were recruited in the study. Three polymorphisms (rs2074404 GG/GT/TT, rs17425622 CC/CT/TT, rs34043159 CC/CT/TT) in genes linked to inflammation in all the subjects were genotyped by using the Sequenom iPLEX Assay.Results: The allele G of WNT3 rs2074404 can increase risk on PD (OR: 1.048, 95% CI: 1.182–1.333, p = 0.006), exclusively in the LOPD subgroup (OR: 1.166, 95% CI:1.025–1.327, p = 0.019), but not in EOPD or MSA. And the recessive model analysis also demonstrated an increased PD risk in GG genotype of this locus (OR = 1.331, p = 0.007). However, no significant differences were observed in the genotype distributions and alleles of HLA-DRB5 rs17425622 and IL1R2 rs34043159 between the PD patients and controls, between the MSA patients and controls, or between subgroups of PD or MSA and controls.Conclusion: Our results suggested the allele G of WNT3 rs2074404 have an adverse effect on PD and particularly, on the LOPD subgroup among a Chinese population.

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Single Nucleotide Polymorphisms Associated With Gut Homeostasis Influence Risk and Age-at-Onset of Parkinson's Disease

Cited by 19 publications

References 86 publications

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

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

Intestinal Inflammation and Parkinson’s Disease

Association Analysis of WNT3, HLA-DRB5 and IL1R2 Polymorphisms in Chinese Patients With Parkinson’s Disease and Multiple System Atrophy

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