Genetic risk of Parkinson disease and progression:

Abstract

ObjectiveTo determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression.MethodsWe evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed.ResultsWe confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69–6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04–20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16–1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21–1.03]).ConclusionsThis study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

“…It is highly relevant to note that GPNMB has a neuroprotective role for TDP43 toxicity or ALS [127, 199]. GPNMB was also described as neurodegeneration biomarker in Alzheimer’s, Parkinson’s, Gaucher’s disease and PLOSL leukodystrophy [79, 82, 124, 126, 173].…”

The Emerging Functions of LRRK2 and Rab GTPases in the Endolysosomal System

“…In addition, dysregulation of endolysosomal system has been implicated more broadly in familial and sporadic PD other than LRRK2-related PD. For instance, the lysosomal enzyme glucocerebrosidase (GBA) and the lysosomal K + channel TMEM175 are well-validated risk factors identified by GWAS of sporadic PD (Nalls et al, 2014;Chang et al, 2017;Blauwendraat et al, 2019;Iwaki et al, 2019). Also, the lysosomal P-type ATPase ATP13A2 (PARK9) and the retromer complex component VPS35 (PARK17) regulating endosome-to-Golgi transport are the products of the causative genes for familial PD or related diseases (Ramirez et al, 2006;Vilariño-Güell et al, 2011;Zimprich et al, 2011).…”

Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy

“…G2019S can cause familial PD, although often with reduced penetrance. Recently, the LRRK2 PD risk-associated SNP, rs76904798, has also been associated with the rate of progression of PD [9]. LRRK2 is expressed in multiple human tissues including brain and whole blood.…”