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

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

doi:10.3389/fnagi.2020.603849

Abstract

Research is increasingly focusing on gut inflammation as a contributor to Parkinson's disease (PD). Such gut inflammation is proposed to arise from a complex interaction between various genetic, environmental, and lifestyle factors, however these factors are under-characterized. This study investigated the association between PD and single-nucleotide polymorphisms (SNPs) in genes responsible for binding of bacterial metabolites and intestinal homeostasis, which have been implicated in intestinal infections or inflammatory bowel disease. A case-control analysis was performed utilizing the following cohorts: (i) patients from the Australian Parkinson's Disease Registry (APDR) (n = 212); (ii) a Caucasian subset of the Parkinson's Progression Markers Initiative (PPMI) cohort (n = 376); (iii) a combined control group (n = 404). The following SNPs were analyzed: PGLYRP2 rs892145, PGLYRP4 rs10888557, TLR1 rs4833095, TLR2 rs3804099, TLR4 rs7873784, CD14 rs2569190, MUC1 rs4072037, MUC2 rs11825977, CLDN2 rs12008279 and rs12014762, and CLDN4 rs8629. PD risk was significantly associated with PGLYRP4 rs10888557 genotype in both cohorts. PGLYRP2 rs892145 and TLR1 rs4833095 were also associated with disease risk in the APDR cohort, and TLR2 rs3804099 and MUC2 rs11825977 genotypes in the PPMI cohort. Interactive risk effects between PGLYRP2/PGLYRP4 and PGLYRP4/TLR2 were evident in the APDR and PPMI cohorts, respectively. In the APDR cohort, the PGLYRP4 GC genotype was significantly associated with age of symptom onset, independently of gender, toxin exposure or smoking status. This study demonstrates that genetic variation in the bacterial receptor PGLYRP4 may modulate risk and age-of-onset in idiopathic PD, while variants in PGLYRP2, TLR1/2, and MUC2 may also influence PD risk. Overall, this study provides evidence to support the role of dysregulated host-microbiome signaling and gut inflammation in PD, and further investigation of these SNPs and proteins may help identify people at risk of developing PD or increase understanding of early disease mechanisms.

Highlights

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder with no cure
There was no significant difference in gender distribution between control, Australian Parkinson’s Disease Registry (APDR) and Parkinson’s Progression Markers Initiative (PPMI) cohorts, gender was included in all corrected models due to the presence of some X-linked single-nucleotide polymorphisms (SNPs)
Polymorphisms in other microbial pattern recognition receptors and one intestinal mucin were associated with PD risk; where PGLRYP2 rs892145 and Toll like receptor 1 (TLR1) rs4833095 were significant in the APDR cohort, while Toll like receptor 2 (TLR2) rs3804099 and Mucin 2 (MUC2) rs11825977 were significant in the PPMI cohort

Summary

Introduction

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder with no cure. diagnosis and treatment typically center around motor impairments, PD is viewed as a complex, heterogeneous condition with a plethora of non-motor symptoms (Sauerbier et al, 2016; Ferreira and Massano, 2017). Alpha-synuclein aggregation and phosphorylation throughout the enteric nervous system have been reported in people with PD (Braak et al, 2006) sometimes up to 20 years before PD diagnosis (Stokholm et al, 2016), but are not specific to PD (Visanji et al, 2015; Corbillé et al, 2016). Alpha-synuclein levels are increased throughout the enteric neurons of children with intestinal inflammation (Stolzenberg et al, 2017), adults with Crohn’s disease (Prigent et al, 2019) and a high proportion of healthy individuals without a known neurodegenerative diagnosis during life (Gold et al, 2013), supporting a proposed role of alpha-synuclein in normal gut function and immunity (Barbut et al, 2019). The gut is implicated in early inflammatory processes that may contribute to alpha-synuclein aggregation and PD pathology in susceptible individuals (Hawkes et al, 2007; Houser and Tansey, 2017; Johnson et al, 2018), the exact mechanisms are still unclear

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