Aug 2026· Journal of Parkinson's Disease· pp.
1877718X261452773
· 0 citations· 28 references
Medicine
TL;DR
SLC25A46 variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.
Abstract
BackgroundThe SLC25A46 gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in SLC25A46 have been described in patients with Parkinson's disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited.ObjectiveTo assess whether SLC25A46 variants contribute to PD, REM sleep behavior disorder (RBD), or dementia with Lewy bodies (DLB).MethodsWe examined common variants using four representative PD genome-wide association studies (GWAS) and an RBD GWAS and applied summary-data-based Mendelian randomization (SMR) to evaluate whether genetically regulated expression of SLC25A46 shows a causal association with the risk of PD or RBD. Rare variant analyses were conducted in four cohorts of European descent: Accelerating Medicines Partnership: Parkinson's Disease (AMP-PD) PD (3,051 PD, 3,667 controls), UK Biobank (3,267 PD, 14,939 proxy, 54,800 controls), RBD (1,376 RBD, 2,580 controls), and AMP-PD DLB (2,605 DLB, 1,894 controls). Optimal sequence kernel association test (SKAT-O) and meta-analysis were used to assess rare variants.ResultsNo associations were observed between SLC25A46 variants and PD, RBD, or DLB. SMR analyses revealed no evidence supporting a causal relationship between SLC25A46 expression and PD or RBD risk. Rare variant burden analyses did not identify significant associations after multiple-testing correction across cohorts or meta-analyses.ConclusionSLC25A46 variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.
Background An X-linked levodopa-responsive parkinsonism-epilepsy syndrome has been associated with PGK1, and the gene lies within the previously suspected PD locus PARK12. Objective To examine the association of common and rare PGK1 variants with PD. Methods We analyzed common and rare variants from Accelerated Medicines Partnership - Parkinsons Disease (AMP-PD) and UK Biobank (UKBB, total N=4,523 PD cases, 19,736 proxy cases, and 390,532 controls). To account for the X-linked location of PGK1, we used sex-stratified, combined regression models and optimized sequence Kernel association (SKAT-O) tests, followed by meta-analysis using MetaSKAT. Results We found no association between common or rare PGK1 variants and PD in sex-stratified or combined analyses, including after cross-cohort meta-analysis. Conclusion Although we did not find evidence supporting an association between PGK1 and PD, very rare pathogenic PGK1 variants may still contribute to syndromic parkinsonism. Future research could explore larger datasets to further examine this potential association.
L. V. Chifamba, S. C. Parlar, L. Liu et al.· medRxiv· 0 citations
Genetic variants in
GBA1
, encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the strongest genetic risk factor for Parkinson’s disease (PD) and provide a mechanistic link between Gaucher disease (GD) and PD. While biallelic
GBA1
mutations cause GD, heterozygous variants confer an increased, age-dependent risk of PD, with mutation-specific differences in penetrance, age at onset, cognitive decline, and survival. This review critically examines the molecular and clinical spectrum of
GBA1
-associated PD (GBA1-PD), highlighting the relationship between variant severity, lysosomal dysfunction, and disease progression. We discuss two major, partially overlapping pathogenic frameworks underlying
GBA1
-PD: loss-of-function mechanisms associated with reduced GCase activity, glycosphingolipid accumulation, and impaired autophagy–lysosomal pathways, and toxic gain-of-function mechanisms driven by mutant GCase misfolding, endoplasmic reticulum stress, and proteostatic imbalance. Increasing evidence suggests that these mechanisms converge on α-synuclein aggregation and dopaminergic neurodegeneration. We further summarize emerging disease-modifying therapeutic strategies, including small-molecule GCase activators, pharmacological chaperones, substrate reduction therapies, acid ceramidase inhibitors, and gene therapies. Although clinical outcomes have been heterogeneous,
GBA1
-associated PD represents a valuable model for precision medicine, illustrating how genetic stratification can guide mechanism-based therapeutic development in neurodegeneration.
Christiane Oleksy, I. Boussaad, Z. Landoulsi et al.· npj Parkinson's Disease· 0 citations
Background Transmembrane protein 106B (TMEM106B) variations not only act as genetic modifiers of the risk of developing frontotemporal lobar degeneration but also correlate with the heterogeneity of clinicopathological phenotypes in other neurodegenerative diseases. However, the roles of TMEM106B in Parkinson’s disease (PD) are sparsely explored. This study aims to explore whether TMEM106B variants influence the trajectories of clinical phenotypes in PD. Methods We longitudinally followed 241 PD patients and genotyped their single nucleotide polymorphism (SNP) of rs3173615. Patients were categorized according to rs3173615 genotypes into GG (major allele homozygotes), GC (heterozygotes), and CC (minor allele homozygotes) groups. All patients completed clinical evaluations and neuropsychological tests at baseline and every follow-up. Linear mixed-effects models were adopted to evaluate the association between rs3173615 genotypes and longitudinal disease progression in PD. Results At baseline, both the GG and GC groups presented less severe excessive daytime sleepiness than the CC group, and no association between the remaining clinical characteristics and the genotypes of rs3173615 was observed among the three groups. Longitudinally, compared with the CC group, the GC group manifested a significantly faster exacerbation of depression, visuospatial function and quality of life (QoL), and the GG group showed the same tendency as the GC group, though without statistical significance. Conclusion TMEM106B rs3173615 is a genetic modifier for the trajectory of depression, visuospatial function and QoL in PD. Our findings suggest the potential involvement of TMEM106B in the pathogenesis of disease progression in PD, especially in the deterioration of depression, cognition and QoL.
Wanbing Zhao, Xiaoniu Liang, Bolin Hu et al.· Frontiers in Aging Neuroscie...· 0 citations
Background α-Synucleinopathies are clinically and biologically heterogeneous disorders lacking reliable biomarkers to assist with early diagnosis, disease progression, patient stratification, and therapeutic targeting. Genetic variation is known to impact biomarker levels, influencing their utility and interpretation in research and clinical settings. We aimed to identify common genetic modulators of biomarker levels implicated in α-synucleinopathy pathogenesis. Methods 63 CSF, plasma, and urine biomarkers were analyzed in 581 individuals from the Parkinson’s Progression Markers Initiative (PPMI). GWAS was performed to test for associations with common variants, while regressions and area under the curve (AUC) analysis was used to assess predictive power. Analyses were adjusted for age, sex, disease status, and principal components. PD- and DLB-risk loci associations were separately assessed for each GWAS. Results We confirm strong associations between urine bis(monoacylglycerol)phosphate (BMP) isoforms and the variants LRRK2 p.G2019S and GBA1 p.N370S, while providing support for BMPs use as a LRRK2-PD biomarker. CSF Aβ was significantly associated with an APOE ε4 allele, reinforcing its central role in amyloid regulation. Novel associations were detected between CSF ceramide isoforms the MCF2L2 and GMNN loci, and between CSF tau and the TP63 locus. Multiple PD risk loci, including MAPT, SIPA1L2, MCCC1, and RAB29, were associated with lysosomal lipid biomarkers, highlighting pathway-level convergence. Conclusions The present study reveals established and novel genetic modulators of potential α-synucleinopathy biomarkers, demonstrating that genetic background significantly shapes biomarker levels. These genetic influences should be accounted for when conducting biomarker-based research, clinical trials, or therapeutic development to ensure accurate interpretation and improve their translational relevance.
E. Somerville, Lang Liu, Michael Ta et al.· Research Square· 0 citations
Abstract Mutations in the glucocerebrosidase (GBA) gene, originally implicated in Gaucher’s disease, are now recognized as a major risk factor for developing Parkinson’s disease (PD). While up to 70% of PD patients eventually progress to dementia, GBA mutations further increase the risk of Lewy body dementias (LBD), an umbrella term encompassing both dementia with Lewy bodies and Parkinson’s disease dementia. Collectively, these disorders are classified as synucleinopathies. To date, there is no clear understanding of the mechanistic relationships between GBA mutations and synucleinopathies, although, synaptic protein changes have been shown to correlate with cognitive change in LBD as well as in Alzheimer’s disease (AD). The aim of this study was to examine synaptic dysfunction in α-synucleinopathies with GBA mutations. The research cohort consisted of 10 controls, 7 PD/LBD-GBA N370S, and 20 PD/LBD-wild type (WT) where seven synaptic markers including four pre-synaptic [synaptosomal-associated protein 25; (SNAP25), synaptophysin; (SYP), ras-related protein; (Rab3A), and vesicle associated membrane proteins 2; (VAMP2)], two post-synaptic [post-synaptic density protein 95; (PSD95), and neurogranin; (NRGN)], and one astrocytic [vesicle associated membrane proteins 3; (VAMP3)] protein were investigated in four cortical regions (prefrontal, temporal, anterior cingulate and parietal) using immunoblot technique. Four markers (NRGN, SNAP25, VAMP2, and VAMP3) were found to be significantly and regionally altered between the three groups. The expression of pre-synaptic (SNAP25), post-synaptic (NRGN), and the astrocytic protein (VAMP3) is different between PD/LBD with GBA mutation and PD/LBD-WT suggesting the potential role of GBA gene due to mutations which could alter the levels of some synaptic markers. Our study is the first to validate several synaptic markers in human post-mortem-associated GBA N370S mutation.
Thamir M. Eid, T. Lashley, Thomas T. Warner et al.· Brain Communications· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
