Neurobiology of Aging

Oxidative stress has been implicated in Parkinsons disease (PD). Genes involved in PD, such as PRKN, PINK1 and PARK7, contribute to oxidative stress in dopaminergic neurons. The X-linked G6PD gene encodes glucose 6-phosphate dehydrogenase, an important regulator of oxidative stress. Recent studies suggested that alpha-synuclein aggregates may impair G6PD activity and contribute to dopaminergic neuron loss, and that G6PD mutations may independently increase the risk of PD. In this study, we aimed...

Variants in PGLYRP2, particularly rs892145-T, have been suggested as Parkinsons disease (PD) risk factors. We analyzed data from 31,334 PD patients and 17,772 controls across diverse ancestries. A significant sex-dependent effect of rs892145-T was observed in African (AFR) ancestry males (OR=0.73, 95%CI: 0.57-0.94, p=0.014). Gene-based analyses identified another variant, rs7251871-A, as significantly associated with PD in AFR males (OR=1.34, 95%CI:1.13-1.59, p=6.65E-04, Bonferroni p=0.0432). No...

The objective of our study was to investigate the impact of the mitochondrial polygenic score (MGS) and lifestyle/environmental data on age at onset in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic Parkinsons disease (iPD). In this study, we included N=486 patients with LRRK2-PD and N=9259 patients with iPD from AMP-PD, Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data was utilized to perform the MGS analysis, using 14 Single Nucleotide Polymorphisms (SNPs)...

Rare mutations in genes originally discovered in multi-generational families have been associated with increased risk of Parkinsons Disease (PD). The involvement of rare variants in DNAJC13, UCHL1, HTRA2, GIGYF2 and EIF4G1 loci have been poorly studied or produced conflicting results across cohorts. However, they are still being often referred to as "PD-genes" and used in different models. To further elucidate the role of these five genes in PD, we fully sequenced them using molecular inversion ...

Previous studies have suggested that rare biallelic SYNJ1 mutations may cause autosomal recessive parkinsonism and Parkinsons disease (PD). Our study explored the impact of rare SYNJ1 variants in non-familial settings, including 8,165 PD cases, 818 early-onset PD (EOPD, <50 years) and 70,363 controls. Burden meta-analysis using optimized sequence Kernel association test (SKAT-O) revealed an association between rare nonsynonymous variants in the Sac1 SYNJ1 domain and PD (Pfdr=0.040). Additionally...

The PSAP gene encodes prosaposin, which is later cleaved into four active saposins: saposin A, B, C and D. Mutations in these enzymes have been linked to specific lysosomal storage disorders. Recently, a genetic association between mutations in saposin D and Parkinsons disease (PD) has been reported. To further examine whether variants in saposin D or the other saposins could be associated with Parkinsons disease, we performed Optimized Sequence Kernel Association Test (SKAT-O) in 4,132 Parkinso...

BackgroundBiallelic PRKN mutation carriers with Parkinsons disease (PD) typically have an earlier disease onset, slow disease progression and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial. ObjectivesWe aimed to examine the association between heterozygous PRKN variants, including single nucleotide variants and copy-number variations, and PD. MethodsWe fully sequenced PRKN in 2,809 PD patient...

BackgroundDNAJC13 was initially linked to autosomal dominant (AD) Parkinsons disease (PD) in a European Mennonite family carrying the p.N855S variant. However, imperfect segregation and conflicting reports of pathogenicity raised uncertainty of DNAJC13s role in the disease. ObjectivesExplore the association between common and rare variants in DNAJC13 and Parkinsons disease. MethodsWe leveraged the largest available PD genetics data from the Accelerating Medicines Partnership - Parkinson Diseas...

To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association (P = 6.5 x 10-7) that was replicated in additional Japanese samples (P = 2.9 x 10-6. OR = 1.58; 95% confidence interval, 1.30 to 1.91), an...

Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). The majority of patients with isolated rapid eye movement sleep behavior disorder (iRBD) develop PD or DLB later in life, suggesting that iRBD is a prodromal phase of these two conditions. In the current study we aimed to evaluate the role of SMPD1 variants in iRBD. SMPD1 and its untranslated regions were sequenced using targeted next-gen...

BackgroundSeveral rare and common variants are associated with Parkinsons disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinsons disease. To address this issue, we investigated whether a PRS calculated from significant GWAS SNPs affects the penetrance of Parkinsons disease among carriers of rare monogenic variants in known Parkinsons disease genes and those with a family history. MethodsWe calculated the PRS based on common variants...

GBA1 variants and decreased glucocerebrosidase (GCase) activity are implicated in Parkinsons disease (PD). We investigated the hypothesis that increased levels of glucosylceramide (GlcCer), one of GCase main substrates, are involved in PD pathogenesis. Using multiple genetic methods, we show that ATP10D, not GBA1, is the main regulator of plasma GlcCer levels, yet it is not involved in PD pathogenesis. Plasma GlcCer levels were associated with PD, but not in a causative manner, and are not predi...

ObjectiveTo study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration. MethodsA total of 4,147 individuals were included: 1,061 iRBD patients and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk for iRBD, age at onset (AAO) and conversion rates. ResultsGBA variants were found in 9.5% of iRBD patients c...

In 2013, the ALFA (ALzheimer and FAmilies) project was established to investigate pathophysiological changes in preclinical Alzheimers disease (AD), and to foster research on early detection and preventive interventions. Since then, it has prospectively followed cognitively unimpaired late/middle-aged participants, most of whom are adult children of AD patients. Risk stratification of cognitively unimpaired individuals, including genetic factors is key for implementing AD prevention strategies. ...

NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Nieman-Pick disease type C, a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinsons disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement (RE...

Background and ObjectivesThe two most common neurodegenerative diseases are Alzheimers disease (AD) and Parkinsons disease (PD), both related to age and affect millions of people across the world, especially as life expectancy increases in certain countries. Here, we explore the potential predictiveness of the genetic risk of AD and PD separately and then the extent of the underlying shared genetics of AD and PD. MethodsThe population genetic risk estimates for AD and PD were derived using a pr...

ObjectiveTo identify genetic factors that may modify the effects of the MAPT locus in Parkinsons disease (PD). MethodsWe used data from the International Parkinsons Disease Genomics Consortium (IPDGC) and the UK biobank (UKBB). We stratified the IPDGC cohort for carriers of the H1/H1 genotype (PD patients n=8,492 and controls n=6,765) and carriers of the H2 haplotype (with either H1/H2 or H2/H2 genotypes, patients n=4,779 and controls n=4,849) to perform genome-wide association studies (GWASs)....

IntroductionEpidemiological studies suggest that patients with Parkinsons disease (PD) may have lower levels of vitamin B12 compared to healthy controls, and it was proposed that PD patients could benefit from vitamin B12 supplementation. Functional studies have shown that B12 could modify LRRK2 activity and may directly interact with alpha-synuclein. This study aimed to investigate the role of common and rare variants in genes related to B12 metabolism and assess the potential causal relationsh...

BackgroundMutations within the genes PRKN and PINK1 are the leading cause of early onset autosomal recessive Parkinsons disease (PD). However, the genetic cause of most early-onset PD (EOPD) cases still remains unresolved. Long-read sequencing has successfully identified many pathogenic structural variants that cause disease, but this technology has not been widely applied to PD. We recently identified the genetic cause of EOPD in a pair of monozygotic twins by uncovering a complex structural va...

Alpha-Synuclein (-Syn) is the main protein component of Lewy bodies (LB), the pathological hallmark of Parkinsons disease (PD). Cerebrospinal fluid (CSF) levels of -Syn are not currently used as a clinical biomarker but may be a proxy for pathological -Syn accumulation in the brain. Therefore, identifying genetic modifiers of CSF -Syn levels could provide insights into the underlying molecular mechanisms leading to PD. However, genetic modifiers of CSF -Syn levels remain unknown. CSF levels of a...