Risk Of Sporadic Parkinson's Disease Research Articles

Quantitative assessment of the effect of FGF20 rs1721100 and rs12720208 variant on the risk of sporadic Parkinson's disease: a meta-analysis.

While many studies have investigated the associations between fibroblast growth factor 20 (FGF20) rs1721100 (C/G) and rs12720208 (C/T) polymorphisms and susceptibility to Parkinson's disease (PD), their results are controversial. Our present meta-analysis estimated the overall association between FGF20 rs1721100 and rs12720208 polymorphisms and the risk of sporadic PD. We performed a comprehensive literature search of the PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure, and Wanfang Medicine electronic databases, which was updated in April 2021. Based on strict inclusion and exclusion criteria, the analysis included a total of 10 papers involving 14 studies with 5262 cases of PD and 6075 controls. Review Manager 5.4 software was used to assess the available data from each study. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between the FGF20 rs1721100 and rs12720208 polymorphisms and sporadic PD risk. Our results showed that the FGF20 rs1721100 G allele frequency and genotype distribution did not differ between PD patients and controls. Similarly, the FGF20 rs12720208 T allele frequency and genotype distribution did not differ significantly between the two groups. A subgroup analysis of Asian and Caucasian populations also showed the same results. The results of this meta-analysis indicated that neither the rs1721100 C/G nor the rs12720208 C/T variants were associated with sporadic PD susceptibility.

Analysis of rare variants of autosomal-dominant genes in a Chinese population with sporadic Parkinson's disease.

BackgroundTo date, several studies have suggested that genes involved in monogenic forms of Parkinson's disease (PD) contribute to unrelated sporadic cases, but there is limited evidence in the Chinese population.MethodsWe performed a systematic analysis of 12 autosomal‐dominant PD (AD‐PD) genes (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, DNAJC13, CHCHD2, HTRA2, NR4A2, RIC3, TMEM230, and UCHL1) using panel sequencing and database filtration in a case‐control study of a cohort of 391 Chinese sporadic PD patients and unrelated controls. We evaluated the association between candidate variants and sporadic PD using gene‐based analysis.ResultsOverall, 18 rare variants were discovered in 18.8% (36/191) of the index patients. In addition to previously reported pathogenic mutations (LRRK2 p.Arg1441His and p.Ala419Val), another four unknown variants were found in LRRK2, which also contribute to PD risk (p = 0.002; odds ratio (OR) = 7.83, 95% confidence intervals (CI) = 1.76–34.93). The cumulative frequency of undetermined rare variants was significantly higher in PD patients (14.1%) than in controls (3.5%) (p = 0.0002; OR=4.54, 95% CI = 1.93‐10.69).ConclusionOur results confirm the strong impact of LRRK2 on the risk of sporadic PD, and also provide considerable evidence of the existence of additional undetermined rare variants in AD‐PD genes that contribute to the genetic etiology of sporadic PD in a Chinese cohort.

Genetic analysis of N6-methyladenosine modification genes in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease with a relatively unclear etiology. Previous studies have shown that N6-methyladenosine (m6A) is a vital RNA modification enriched in brain tissue, and that the genes involved in m6A modification are implicated in various neurologic diseases. Here, we conducted a comprehensive genetic analysis using targeted sequencing with molecular inversion probes (MIPs) to identify m6A-modification genes (including METTL3, METTL14, WTAP, FTO, ALKBH5, YTHDF1, YTHDF2, YTHDF3, HNRNPC, and ELAVL1) in a total of 1647 sporadic PD patients and 1372 controls of Han Chinese origin. PD patients were divided into early-onset PD (EOPD) and late-onset PD (LOPD) based on whether the onset of motor symptoms occurred before or after 50 years of age. Rare variants were subjected to gene-based burden tests and common variants were subjected to single-variant association analyses. As a result, we identified 214 rare variants in all 10 m6A-modification genes and 16 common variants in 7 genes. Gene-wise association analyses of rare variants in each m6A-modification gene did not achieved a p value of less than 0.05 in either total cohorts or 2 age groups. In fact, p values greater than 0.05 were found when conducting single-variant association analyses on common variants of these genes between PD and control patients. Our comprehensive analyses of m6A-modification genes suggest that there is no significant association between these 10 m6A-modification genes and the risk of sporadic PD.

Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease

Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including genes with known PD associations and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1-null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research.

Alpha-Synuclein Expression in Patients with Parkinson's Disease: A Clinician's Perspective

Although physiological function of alpha-synuclein is not yet clearly understood, accumulating evidence strongly suggests it plays a crucial role in the pathogenesis of Parkinson disease. Pathologically, alpha-synuclein is a major component of Lewy bodies, which is the pathological hallmark of Parkinson disease. Alpha-synuclein pathology is observed in the brainstem nuclei, including the dorsal motor nucleus of the vagus nerve, the locus ceruleus, and the substantia nigra in the early phase of Parkinson disease and it may 'spread' to cerebral cortical areas in the advanced Parkinson disease and appears to have a role in the cognitive decline in Parkinson disease. Recently, it is suggested that alpha-synuclein pathology in Parkinson disease starts in the olfactory bulb or enteric nervous system and then spreads to the brainstem. In accordance with this hypothesis, alpha-synuclein pathology has been found in gastric mucosa and colonic mucosa of patients with Parkinson disease. Genetically, SNCA mutations including point mutation and copy number variation are known to cause familial Parkinson disease, further supporting the assumption that alpha-synuclein plays a crucial role in Parkinson disease pathogenesis. In addition, recent GWAS studies consistently show that the SNPs in SNCA genes are associated with risk for sporadic Parkinson disease. It is also known that variations in the promoter region or 3'UTR of SNCA, which increases the expression of SNCA, are associated with the risk for Parkinson disease. Collectively, these findings suggest that further studies on alpha-synuclein will lead to the elucidation of the mechanism of and therapy for Parkinson disease.

The modulation of Amyotrophic Lateral Sclerosis risk by Ataxin-2 intermediate polyglutamine expansions is a specific effect

Full expansions of the polyglutamine domain (polyQ≥34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27≤polyQ≤33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30≤polyQ≤35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor.

Comprehensive sequencing of the LRRK2 gene in patients with familial Parkinson's disease from North Africa

The LRRK2 gene is a key player in Parkinson's disease (PD), however prevalence and pathogenicity of LRRK2 variants remain to be investigated in ethnically diverse populations. Herein, we performed comprehensive sequencing of the LRRK2 gene in 92 Tunisian probands with familial PD. We then performed an association study using all identified variants in a series of 167 Lrrk2 p.G2019S-negative patients with sporadic PD and 365 Lrrk2 p.G2019S-negative healthy control subjects, all from the same Arab-Berber ethnicity. We identified one novel coding substitution (p.M2408I) and 24 known coding changes. Only the Lrrk2 p.G2019S mutation segregated with disease within families and was found in 39% of familial probands. None of the variants displayed significant association with risk for sporadic PD, however a trend was observed for Lrrk2 p.Y2189C. The present study underscores the importance of the LRRK2 gene in the Tunisian PD population.

JNK3 Mediates Paraquat- and Rotenone-Induced Dopaminergic Neuron Death

Mechanistic studies underlying dopaminergic neuron death may identify new drug targets for the treatment of Parkinson disease. Epidemiological studies have linked pesticide exposure to increased risk for sporadic Parkinson disease. Here, we investigated the role of c-Jun-N-terminal kinase 3 (JNK3), a neural-specific JNK isoform, in dopaminergic neuron death induced by the pesticides rotenone and paraquat. The role of JNK3 was evaluated using RNA silencing and gene deletion to block JNK3 signaling. Using an antibody that recognizes all isoforms of activated JNKs, we found that paraquat and rotenone stimulate JNK phosphorylation in primary cultured dopaminergic neurons. In cultured neurons transfected with Jnk3-specific siRNA and in neurons from Jnk3 mice, JNK phosphorylation was nearly abolished, suggesting that JNK3 is the main JNK isoform activated in dopaminergic neurons by these pesticides. Paraquat- and rotenone-induced death of dopaminergic neurons was also significantly reduced by Jnk3 siRNA or Jnk3 gene deletion, and deletion of the Jnk3 gene completely attenuated paraquat-induced dopaminergic neuron death and motor deficits in vivo. Our data identify JNK3 as a common and critical mediator of dopaminergic neuron death induced by paraquat and rotenone, suggesting that it is a potential drug target for Parkinson disease treatment.

P3.029 Polymorphisms in aldehyde dehydrogenase and the risk of sporadic Parkinson disease

P3.029 Polymorphisms in aldehyde dehydrogenase and the risk of sporadic Parkinson disease

Genetic variability in the mitochondrial serine proteaseHTRA2contributes to risk for Parkinson disease

In one genetic study, the high temperature requirement A2 (HTRA2) mitochondrial protein has been associated with increased risk for sporadic Parkinson disease (PD). One missense mutation, p.Gly399Ser, in its C-terminal PDZ domain (from the initial letters of the postsynaptic density 95, PSD-95; discs large; and zonula occludens-1, ZO-1 proteins [Kennedy, 1995]) resulted in defective protease activation, and induced mitochondrial dysfunction when overexpressed in stably transfected cells. Here we examined the contribution of genetic variability in HTRA2 to PD risk in an extended series of 266 Belgian PD patients and 273 control individuals. Mutation analysis identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. Moreover, we identified six patient-specific variants in 5' and 3' regulatory regions that might affect HTRA2 expression as supported by data of luciferase reporter gene analyses. Our study confirms a role of the HTRA2 mitochondrial protein in PD susceptibility through mutations in its functional PDZ domain. In addition, it extends the HTRA2 mutation spectrum to functional variants possibly affecting transcriptional activity. The latter underpins a previously unrecognized role for altered HTRA2 expression as a risk factor relevant to parkinsonian neurodegeneration.

Relative Sensitivity of Parkin and Other Cysteine-containing Enzymes to Stress-induced Solubility Alterations

Loss of parkin function is a predominant cause of familial Parkinsonism. Emerging evidence also suggests that parkin expression variability may confer a risk for sporadic Parkinson disease. We have recently demonstrated that a wide variety of Parkinson disease-linked stressors, including dopamine (DA), induce parkin solubility alterations and promote its aggregation within the cell, a phenomenon that may underlie the progressive susceptibility of the brain to degeneration. The vulnerability of parkin to stress-induced modification is likely due to its abundance of cysteine residues. Here, we performed a comprehensive mutational analysis and demonstrate that Cys residues residing both within and outside of the RING-IBR (in between RING fingers)-RING domain of parkin are important in maintaining its solubility. The majority of these Cys residues are highly conserved in parkin across different species and potentially fulfil important structural roles. Further, we found that both parkin and HHARI (human homologue of Drosophila ariadne), another RING-IBR-RING-type ubiquitin ligase, are comparably more susceptible to solubility alterations induced by oxidative and nitrosative stress when compared with other non-RING-IBR-RING Cys-containing enzymes. However, parkin appears to be uniquely sensitive to DA-mediated stress, the specificity of which is likely due to DA modification of 2 Cys residues on parkin (Cys-268 and Cys-323) that are distinct from other RING-IBR-RING members.