Parkinson's Disease Susceptibility Research Articles

Peripheral immune cell abundance differences link blood mitochondrial DNA copy number and Parkinson's disease.

Mitochondrial dysfunction plays an important role in Parkinson's disease (PD), with mitochondrial DNA copy number (mtDNA-CN) emerging as a potential marker for mitochondrial health. We investigated the links between blood mtDNA-CN and PD severity and risk using the Accelerating Medicines Partnership program for Parkinson's Disease dataset, replicating our results in the UK Biobank. Our findings reveal that reduced blood mtDNA-CN levels are associated with heightened PD risk and increased severity of motor symptoms and olfactory dysfunction. We estimated blood cell composition using complete blood cell profile when available or RNA-sequencing data as a surrogate. After adjusting for blood cell composition, the associations between mtDNA-CN and PD risk and clinical symptoms became non-significant. Bidirectional Mendelian randomization analysis also found no evidence of a direct causal relationship between blood mtDNA-CN and PD susceptibility. Hence peripheral inflammatory immune responses rather than mitochondrial dysfunction underpin these previously identified associations in PD.

Regulatory miR-SNP rs4636297A > G in miR-126 is linked to increased risk of rigidity feature in patients with Parkinson’s disease

Introduction A growing body of strong evidence shows that the dysfunction of miRNAs plays key roles in the development and progression of Parkinson’s disease (PD), however, little data has been reported on the association of their SNPs with PD susceptibility. In this study, we investigated the association of regulatory miR-SNP rs4636297A > G with a functional effect on the expression of miRNA-126, as a key dysregulated miRNA in the PD, with the susceptibility and clinical features of the PD. Methods and materials In current study, we included a population consisting of 120 patients with PD and 120 clinically healthy individuals, and their blood samples were taken. After extracting the DNAs, the genotyping of the miR-SNP rs4636297A > G was done through RFLP-PCR technique. Finally, the association of this SNP with the risk and clinical features of PD was determined. Results Although the results showed that the two groups did not differ significantly in terms of allelic and genotype frequencies, it was clinically found that individuals with genotypes carrying the minor allele G (AG and GG genotypes) of the miR-SNP rs4636297A > G had an increased risk of developing rigidity feature in the PD compared to its homozygous major AA genotype (GG genotype; OR = 5.14, p = 0.038 & GA genotype; OR = 4.32, p = 0.032). Conclusion We report for the first time a significant association of functional regulatory SNP rs4636297A > G in the miR-126 with the Parkinson’s clinicopathology. Therefore, this miR-SNP can have a potential predictive biomarker capacity for rigidity in PD, although this hypothesis needs further investigation in the future.

Genetic Polymorphisms in the HMGCR Gene and Associations with Cognitive Decline in Parkinson's Disease Patients.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor and non-motor symptoms including cognitive impairment and dementia. The etiopathogenesis of PD, as well as its protective and susceptibility factors, are still elusive. 3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is an enzyme regulating cholesterol synthesis. Single-nucleotide polymorphisms (SNPs) in the gene coding HMGCR have recently been correlated with the risk of Alzheimer's disease. Alternative splicing of exon 13 of the HMGCR transcript and its strongly associated HMGCR haplotype 7 (H7: rs17244841, rs3846662, rs17238540) may downregulate protein activity and cholesterol synthesis, with lower low-density lipoprotein cholesterol (LDL) levels associated with PD that may affect cognitive abilities. We genotyped three SNPs in the H7 HMGCR gene in 306 PD patients divided into three groups-without cognitive decline, with mild cognitive impairment (MCI), and with PD dementia-and in 242 healthy participants. A correlation between the rs17238540 genotype and PD susceptibility as well as a minor association between rs3846662 and cognitive status in PD patients was observed; however, the two-sided analysis of these groups did not reveal any significance. We observed a statistically significant elevated high-density lipoprotein cholesterol (HDL) plasma level in the minor allele carriers of rs17238540 and rs17244841 among PD patients. This study should be replicated in a larger population.

COVID-19 and Parkinson’s disease: a single-center study and Mendelian randomization study

To investigate the association between COVID-19 and Parkinson’s disease (PD) via a single-center study and a Mendelian randomization (MR) study. A questionnaire-based survey was conducted among PD patients at a single center from December 7, 2022, to March 10, 2023. Logistic regression analysis was performed to identify the infection-related risk factors. Subsequently, bidirectional two-sample Mendelian randomization was employed to explore the association between COVID-19 and PD. In the cross-sectional analysis, it was found that the prevalence of COVID-19 infection in PD patients was 65.7%. Forty-eight (35.3%) PD patients experienced exacerbation of motor symptoms following COVID-19 infection. Long PD disease duration (≥ 10 years) (OR: 3.327, P = 0.045) and long time since last vaccination (> 12 m) (OR: 4.916, P = 0.035) were identified as significant risk factors related to infection. The MR analysis results supported that PD increases the COVID-19 susceptibility (β = 0.081, OR = 1.084, P = 0.006). However, the MR analysis showed that PD did not increases the COVID-19 severity and hospitalization, and no significant association of COVID-19 on PD was observed. The findings from this cross-sectional study suggest that individuals with PD may experience worsened motor symptoms following COVID-19 infection. Long disease duration (≥10 years) and long time since last vaccination (> 12 m) are identified as important risk factors for infection in these patients. Furthermore, our MR study provides evidence supporting an association between PD and COVID-19 susceptibility.

Regulation of MicroRNA-4697-3p by Parkinson's disease-associated SNP rs329648 and its impact on SNCA112 mRNA.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a multifaceted genetic foundation. Genome-Wide Association Studies (GWAS) have played a crucial role in pinpointing genetic variants linked to PD susceptibility. Current study aims to delve into the mechanistic aspects through which the PD-associated Single Nucleotide Polymorphism (SNP) rs329648, identified in prior GWAS, influences the pathogenesis of PD. Employing the CRISPR/Cas9-mediated genome editing mechanism, we demonstrated the association of the disease-associated allele of rs329648 with increased expression of miR-4697-3p in differentiated SH-SY5Y cells. We revealed that miR-4697-3p contributes to the formation of high molecular weight complexes of α-Synuclein (α-Syn), indicative of α-Syn aggregate formation, as evidenced by Western blot analysis. Furthermore, our study unveiled that miR-4697-3p elevates SNCA112 mRNA levels. The resultant protein product, α-Syn 112, a variant of α-Syn with 112 amino acids, is recognized for augmenting α-Syn aggregation. Notably, this regulatory effect minimally impacts the levels of full-length SNCA140 mRNA, as evidenced by qRT-PCR. Additionally, we observed a correlation between the disease-associated allele and miR-4697-3p with increased cell death, substantiated by assessments including cell viability assays, alterations in cell morphology, and TUNEL assays. Our research reveals that the disease-associated allele of rs329648 is linked to higher levels of miR-4697-3p. This increase in miR-4697-3p leads to elevated SNCA112 mRNA levels, consequently promoting the formation of α-Syn aggregates. Furthermore, miR-4697-3p appears to play a role in increased cell death, potentially contributing to the pathogenesis of PD.

Investigation of the causal association between Parkinson's disease and autoimmune disorders: a bidirectional Mendelian randomization study.

To date, an increasing number of epidemiological evidence has pointed to potential relationships between Parkinson's disease (PD) and various autoimmune diseases (AIDs), however, no definitive conclusions has been drawn about whether PD is causally related to AIDs risk. By employing summary statistics from the latest and most extensive genome-wide association studies (GWAS), we performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between PD and a variety of 17 AIDs, encompassing multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, type 1 diabetes, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and vitiligo. Inverse-variance weighted (IVW) was adopted as the main statistical approach to obtain the causal estimates of PD on different AIDs, supplemented by a series of complementary analyses (weighted median, MR Egger regression, and MR-PRESSO) for further strengthening the robustness of results. Our MR findings suggested that genetically predicted higher liability to PD was causally associated with a decreased risk of irritable bowel syndrome (OR = 0.98; 95% CI: 0.96-0.99; P = 0.032). On the contrary, IVW analysis showed a potential positive correlation between genetically determined PD and the incidence of type 1 diabetes (OR = 1.10; 95%CI: 1.02-1.19; P = 0.010). Subsequent MR tests ended up in similar results, confirming our findings were reliable. Additionally, in the reverse MR analyses, we did not identify any evidence to support the causal relationship of genetic predisposition to AIDs with PD susceptibility. In general, a bifunctional role that PD exerted on the risk of developing AIDs was detected in our studies, both protecting against irritable bowel syndrome occurrence and raising the incidence of type 1 diabetes. Future studies, including population-based observational studies and molecular experiments in vitro and in vivo, are warranted to validate the results of our MR analyses and refine the underlying pathological mechanisms involved in PD-AIDs associations.

Association between Parkinson disease and selenium levels in the body: A systematic review and meta-analysis.

Parkinson disease (PD) is a common neurodegenerative disorder, but its pathogenesis is still not entirely understood. While some trace elements, such as selenium, iron, and copper, are considered pivotal in PD onset due to their role in oxidative stress, the association between selenium concentrations and PD susceptibility remains ambiguous. A systematic review and meta-analysis was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and framed by the Patient, Intervention, Comparison, Outcome paradigm. Data were sourced from 4 prominent electronic databases: PubMed, Embase, Web of Science, and Cochrane Library. Eligible studies must have had a PD case group and a control group, both of which presented data on selenium concentrations. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Of 1541 initially identified articles, 12 studies comprising a total of 597 PD cases and 733 controls were selected for the meta-analysis. Pronounced heterogeneity was observed among these studies. When assessing blood selenium levels, no significant difference was found between patients with PD and the controls. However, when examining the cerebrospinal fluid, selenium levels in PD patients were significantly elevated compared to controls (standard mean difference = 1.21, 95% CI 0.04-2.39, P < .05). Subgroup analyses, sensitivity analyses, and evaluation of publication bias were performed to ensure data robustness. Elevated selenium levels in cerebrospinal fluid may be associated with a higher risk of Parkinson. Further prospective research is required to solidify this potential link and to offer avenues for novel therapeutic interventions or preventive measures.

Association study of S100A9 gene polymorphisms with Parkinson's disease risk and age of disease onset.

Intestinal inflammation is associated with several neurodegenerative diseases, including Parkinson's disease (PD). Intestinal inflammation is also closely related to genetic and environmental factors. S100 calcium-binding protein A9 (S100A9) is also thought to be genetically associated with intestinal inflammation and PD risk. This study investigated the association between S100A9 gene polymorphisms and PD risk and age of disease onset. This study used a case-control method and included 242 PD patients and 242 healthy participants. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed. S100A9 expression in the serum of the patients and controls was detected using reverse transcription‑quantitative PCR (RT-qPCR). The CC genotype and C allele of the rs3014866 polymorphism in S100A9 had significantly higher distribution in PD patients. The recessive and dominant models demonstrated that the patients carrying the rs3014866 C allele had a significantly increased risk of developing PD as compared with patients homozygous for the TT genotype. The generalized linear model results demonstrated that rs3014866 was associated with the age of disease onset independent of environmental exposure factors (smoking and toxins). Furthermore, the S100A9 mRNA transcription level in the patients' serum was significantly higher than that of the controls. Moreover, the serum of patients with the CC genotype had higher S100A9 expression levels. The results combined the relationship between S100A9 and PD susceptibility and age of disease onset. The findings might suggest new ideas for PD clinical diagnosis and treatment.

Associative role of HLA-DRB1 as a protective factor for susceptibility and progression of Parkinson's disease: a Chinese cross-sectional and longitudinal study.

Previous genome-wide association studies investigating the relationship between the HLA-DRB1 and the risk of Parkinson's disease (PD) have shown limited racial diversity and have not explored clinical heterogeneity extensively. The study consisted of three parts: a case-control study, a cross-sectional study, and a longitudinal cohort study. The case-control study included 477 PD patients and 477 healthy controls to explore the relationship between rs660895 and PD susceptibility. The cross-sectional study utilized baseline data from 429 PD patients to examine the correlation between rs660895 and PD features. The longitudinal study included 388 PD patients who completed a 3-year follow-up to investigate the effects of rs660895 on PD progression. In the case-control study, HLA-DRB1 rs660895-G allele was associated with a decreased risk of PD in allele model (adjusted OR=0.72, p = 0.003) and dominant model (AG + GG vs. AA: adjusted OR = 0.67, p = 0.003). In the cross-sectional analysis, there was no association between rs660895 and the onset age, motor phenotype, or initial motor symptoms. In the longitudinal analysis, PD patients with the G allele exhibited a slower progression of motor symptoms (MDS-UPDRS-III total score: β = -5.42, p < 0.001, interaction ptime × genotype < 0.001) and non-motor symptoms (NMSS score: β = -4.78, p = 0.030, interaction ptime × genotype < 0.001). Our findings support HLA-DRB1 rs660895-G allele is a protective genetic factor for PD risk in Chinese population. Furthermore, we also provide new evidence for the protective effect of rs660895-G allele in PD progression.

The Molecular Impact of Glucosylceramidase Beta 1 (Gba1) in Parkinson's Disease: a New Genetic State of the Art.

Parkinson's disease (PD) is a neurodegenerative disorder affecting 2-3% of those aged over 65, characterized by motor symptoms like slow movement, tremors, and muscle rigidity, along with non-motor symptoms such as anxiety and dementia. Lewy bodies, clumps of misfolded proteins, contribute to neuron loss in PD. Mutations in the GBA1 gene are considered the primary genetic risk factor of PD. GBA1 mutations result in decreased activity of the lysosomal enzyme glucocerebrosidase (GCase) resulting in α-synuclein accumulation. We know that α-synuclein aggregation, lysosomal dysfunction, and endoplasmic reticulum disturbance are recognized factors to PD susceptibility; however, the molecular mechanisms connecting GBA1 gene mutations to increased PD risk remain partly unknown. Thus, in this narrative review conducted according to a systematic review method, we aimed to present the main contributions arising from the molecular impact of the GBA1 gene to the pathogenesis of PD providing new insights into potential impacts for advances in the clinical care of people with PD, a neurological disorder that has contributed to the substantial increase in the global burden of disease accentuated by the aging population. In summary, this narrative review highlights the multifaceted impact of GBA1 mutations in PD, exploring their role in clinical manifestations, genetic predispositions, and molecular mechanisms. The review emphasizes the importance of GBA1 mutations in both motor and non-motor symptoms of PD, suggesting broader therapeutic and management strategies. It also discusses the potential of CRISPR/Cas9 technology in advancing PD treatment and the need for future research to integrate these diverse aspects for improved diagnostics and therapies.

A genetic and transcriptomic assessment of the KTN1 gene in Parkinson’s disease risk

Parkinson’s disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. An association has been described between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson’s Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to unaffected individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

Key Non-coding Variants in Three Neuroapoptosis and Neuroinflammation-Related LncRNAs Are Protectively Associated with Susceptibility to Parkinson's Disease and Some of Its Clinical Features.

Research findings show that genetic susceptibility to sporadic Parkinson's disease (PD), a common neurodegenerative disorder, is determined through gene variation of loci involved in its development and pathogenesis. A growing body of strong evidence has revealed that dysfunction of long non-coding RNAs (lncRNAs) plays key roles in the pathogenesis and progression of PD through impairing neuronal signaling pathways, but little is known about the relationship between their variants and PD susceptibility. In this research, we intended to study the relationship between functional SNPs rs12826786C>T, rs3200401C>T, and rs6931097G>A in the key lncRNAs stimulating neuroapoptosis and neuroinflammation in PD, including HOTAIR, MALAT1, and lincRNA-P21, respectively, with susceptibility to PD as well as its clinical symptoms.The population of this study consisted of 240 individuals, including 120 controls and 120 cases, and the sample taken from them was peripheral blood. Genotyping of the target SNPs was done using PCR-RFLP. We found that the healthy individuals carry more T allele of MALAT1-rs3200401C>T compared to the patients (P= 0.019). Furthermore, it was observed that in the dominant genetic model, subjects with genotypes carrying the T allele have a lower risk of PD (OR= 0.530; CI= 0.296-0.950; P= 0.033). Regarding the lincRNA-P21-rs6931097G>A, we observed a significant protective relationship between its GA (OR= 0.144; CI= 0.030-0.680; P= 0.014) and AA (OR= 0.195; CI= 00.047-0.799; P= 0.023) genotypes with the manifestation of tremor and bradykinesia symptoms, respectively. Furthermore, the findings indicated that the minor TT genotype of HOTAIR-rs12826786C>T was significantly associated with a reduced risk of bradykinesia symptoms (OR= 0.147; CI= 0.039-0.555; P= 0.005). Collectively, these findings suggest that MALAT1-rs3200401C>T may be an important lncRNA SNP against the development of PD, while the other two SNPs show protective effects on the clinical manifestations of PD in a way that lincRNA-P21-rs6931097G>A has a protective effect against the occurrence of tremor and bradykinesia symptoms in PD patients, and HOTAIR -rs12826786C>T indicates a protective effect against the display of bradykinesia feature. Therefore, they can have valuable potential as biomarkers for clinical evaluations of this disease.

Ethnicity- and sex-specific genome wide association study on Parkinson’s disease

Most previous genome-wide association studies (GWASs) on Parkinson’s disease (PD) focus on the European population. There are several sex-specific clinical differences in PD, but little is known about its genetic background. We aimed to perform an ethnicity-specific and sex-specific GWAS on PD in the Korean population. A total of 1050 PD patients and 5000 controls were included. For primary analysis, we performed a GWAS using a logistic additive model adjusted for age and sex. The same statistical models were applied to sex-specific analyses. Genotyping was performed using a customized microarray chip optimized for the Korean population. Nine single nucleotide polymorphisms (SNPs) including four in the SNCA locus and three from the PARK16 locus were associated with PD in Koreans. The rs34778348 in the LRRK2 locus showed a strong association, though failed to pass cluster quality control. There were no notable genome-wide significant markers near the MAPT or GBA1 loci. In the female-only analysis, rs34778348 in LRRK2 and the four other SNPs in the SNCA showed a strong association with PD. In the male-only analysis, no SNP surpassed the genome-wide significance threshold under Bonferroni correction; however, the most significant signal was rs708726 in the PARK16 locus. This ethnicity- and sex-specific GWAS on PD implicate the pan-ethnic effect of SNCA, the universal but East-Asian inclined effect of PARK16, the East Asian-specific role of LRRK2 G2385R variants, and the possible disproportionate effect of SNCA and PARK16 between sexes for PD susceptibility. These findings suggest the different genetic contributions to sporadic PD in terms of ethnicity and sex.

Membrane phospholipid peroxidation promotes loss of dopaminergic neurons in psychological stress-induced Parkinson's disease susceptibility.

Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that psychological stress promotes PD progression by enhancing glucocorticoids-related oxidative damage, however, the mechanisms involved are unknown. The present study demonstrated that plasma membrane phospholipid peroxides, as determined by phospholipidomics, triggered ferroptosis in dopaminergic neurons, which in turn contributed to stress exacerbated PD-like motor disorder in mice overexpressing mutant human α-synuclein. Using hormonomics, we identified that stress stimulated corticosteroid release and promoted 15-lipoxygenase-1 (ALOX15)-mediated phospholipid peroxidation. ALOX15 was upregulated by α-synuclein overexpression and acted as a fundamental risk factor in the development of chronic stress-induced parkinsonism and neurodegeneration. Further, we demonstrated the mechanism by which corticosteroids activated the PKC pathway and induced phosphatidylethanolamine-binding protein-1 (PEBP1) to form a complex with ALOX15, thereby facilitating ALOX15 to locate on the plasma membrane phospholipids. A natural product isolated from herbs, leonurine, was screened with activities of inhibiting the ALOX15/PEBP1 interaction and thereby attenuating membrane phospholipid peroxidation. Collectively, our findings demonstrate that stress increases the susceptibility of PD by driving membrane lipid peroxidation of dopaminergic neurons and suggest the ALOX15/PEBP1 complex as a potential intervention target.

Deregulation of mTORC1-TFEB axis in human iPSC model of GBA1-associated Parkinson's disease.

Mutations in the GBA1 gene are the single most frequent genetic risk factor for Parkinson's disease (PD). Neurodegenerative changes in GBA1-associated PD have been linked to the defective lysosomal clearance of autophagic substrates and aggregate-prone proteins. To elucidate novel mechanisms contributing to proteinopathy in PD, we investigated the effect of GBA1 mutations on the transcription factor EB (TFEB), the master regulator of the autophagy-lysosomal pathway (ALP). Using PD patients' induced-pluripotent stem cells (iPSCs), we examined TFEB activity and regulation of the ALP in dopaminergic neuronal cultures generated from iPSC lines harboring heterozygous GBA1 mutations and the CRISPR/Cas9-corrected isogenic controls. Our data showed a significant decrease in TFEB transcriptional activity and attenuated expression of many genes in the CLEAR network in GBA1 mutant neurons, but not in the isogenic gene-corrected cells. In PD neurons, we also detected increased activity of the mammalian target of rapamycin complex1 (mTORC1), the main upstream negative regulator of TFEB. Increased mTORC1 activity resulted in excess TFEB phosphorylation and decreased nuclear translocation. Pharmacological mTOR inhibition restored TFEB activity, decreased ER stress and reduced α-synuclein accumulation, indicating improvement of neuronal protiostasis. Moreover, treatment with the lipid substrate reducing compound Genz-123346, decreased mTORC1 activity and increased TFEB expression in the mutant neurons, suggesting that mTORC1-TFEB alterations are linked to the lipid substrate accumulation. Our study unveils a new mechanism contributing to PD susceptibility by GBA1 mutations in which deregulation of the mTORC1-TFEB axis mediates ALP dysfunction and subsequent proteinopathy. It also indicates that pharmacological restoration of TFEB activity could be a promising therapeutic approach in GBA1-associated neurodegeneration.

Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity.

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurotoxicity.

Gene-wide significant association analyses of DNMT1 genetic variants with Parkinson's disease.

Background: DNA methylation plays an important role in Parkinson's disease (PD) pathogenesis. DNA methyltransferase 1 (DNMT1) is critical for maintaining DNA methylation in mammals. The link between DNMT1 polymorphisms and PD remains elusive. Methods: The DNMT1 gene contained a total of 28 single nucleotide polymorphisms (SNPs). Four representing tag-SNPs (rs16999593, rs2162560, rs11880553, and rs9305012) were identified and genotyped in a Han Chinese population comprising 712 PD patients and 696 controls. Association analyses were performed at gene-wide significance (p < 1.8 × 10-3). Results: Rs9305012, but not the other 3 tag-SNPs, was gene-wide significantly associated with PD risk (p = 0.8 × 10-3). The rs9305012/C was a protective allele against PD (p = 1.5 × 10-3, OR 0.786, 95% CI 0.677-0.912). No significant association was observed in individual genders or PD subtypes. Haplotypes of the 4 tag-SNPs showed a significant overall distribution difference between PD patients and controls (p < 1 × 10-4). The 3-allele ACC module in the order of rs2162560, rs11880553, and rs9305012 was the highest-risk haplotype associated with PD (p < 1 × 10-4, OR 2.439, 95% CI 1.563-3.704). Rs9305012 displayed certain probability to affect transcription factor binding and target gene expression based on functional annotation analyses. Conclusion: The DNMT1 variant rs9305012 together with its haplotypes may gene-wide significantly modulate PD susceptibility. Our results support a role of DNMT1 in PD pathogenesis and provide novel insights into the genetic connection in between.

Role and Dysregulation of miRNA in Patients with Parkinson’s Disease

Parkinson's disease (PD) is a neurodegenerative synucleinopathy that has a not yet fully understood molecular pathomechanism behind it. The role of risk genes regulated by small non-coding RNAs, or microRNAs (miRNAs), has also been highlighted in PD, where they may influence disease progression and comorbidities. In this case-control study, we analyzed miRNAs on peripheral blood mononuclear cells by means of RNA-seq in 30 participants, with the aim of identifying miRNAs differentially expressed in PD compared to age-matched healthy controls. Additionally, we investigated the pathways influenced by differentially expressed miRNAs and assessed whether a specific pathway could potentially be associated with PD susceptibility (enrichment analyses performed using the Ingenuity Pathway Analysis tools). Overall, considering that the upregulation of miRNAs might be related with the downregulation of their messenger RNA targets, and vice versa, we found several putative targets of dysregulated miRNAs (i.e., upregulated: hsa-miR-1275, hsa-miR-23a-5p, hsa-miR-432-5p, hsa-miR-4433b-3p, and hsa-miR-4443; downregulated: hsa-miR-142-5p, hsa-miR-143-3p, hsa-miR-374a-3p, hsa-miR-542-3p, and hsa-miR-99a-5p). An inverse connection between cancer and neurodegeneration, called "inverse comorbidity", has also been noted, showing that some genes or miRNAs may be expressed oppositely in neurodegenerative disorders and in some cancers. Therefore, it may be reasonable to consider these miRNAs as potential diagnostic markers and outcome measures.

Association of rare PPARGC1A variants with Parkinson's disease risk.

Recent researches on Parkinson's disease (PD) pathogenesis discovered the correlation between PD and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) dysfunction and reduction of PPARGC1A gene expression. Hence, we detected PPARGC1A rare variants to clarify their effect on PD risk in a large population of PD patients in mainland China. We applied whole-exome sequencing (WES) to 1917 patients with early-onset or familial PD and 1652 controls (WES cohort), and whole-genome sequencing (WGS) to 1962 patients with sporadic late-onset PD and 1279 controls (WGS cohort). To identify PPARGC1A rare variants, we used burden analysis to assess the relationship between PPARGC1A rare variants and PD susceptibility. 30 rare missense variants in the cohort WES and 21 missense variants in the cohort WGS have been detected in the study and PPARGC1A missense variants are significantly associated with early-onset and familial PD susceptibility in our study (P = 0.012), which supports evidence that PPARGC1A rare variants are involved in the onset of early-onset and familial PD. The study suggested that PPARGC1A rare variants may contribute to the risk of early-onset and familial PD.

Association between ABCA7 gene polymorphisms and Parkinson’s disease susceptibility in a northern Chinese Han population

ObjectiveAs a typical member of the ABC transporter superfamily, ABCA7 has been shown to play an important role in stalling the pathogenesis of neurodegenerative disorders through maintaining the normal microglial function, regulating cellular responses to inflammation and ER stress, and modulating lipid metabolism. Variants in the ABCA7 locus have been hypothesized to be correlated with the genetic predisposition of several neurodegenerative disorders. The goal of this study was to examine whether there is a link between three specific single nucleotide polymorphisms in the ABCA7 gene, namely, rs3764650, rs4147929, and rs3752246, with the risk of developing Parkinson’s disease (PD) in a northern Chinese Han community. MethodsIn this case-control study, we recruited 821 participants, including 411 patients with sporadic PD and 410 independent, healthy controls. A Polymerase Chain Reaction-Restriction Fragment Length Polymorphism genotyping assay was used to identify polymorphisms of the three selected single nucleotide polymorphisms (rs3764650, rs4147929, and rs3752246) of the ABCA7 gene. Sanger sequencing was further applied to identify the accuracy of the genotyping results. The chi-square test was used to compare the frequencies of alleles and genotypes in patients and controls. Odds ratios and 95% confidence intervals were calculated using logistic regression. ResultsWe found significant between-group differences in the alleles (A vs. G, nominal P = 0.014) and dominant models (AA + GA vs. GG, nominal P = 0.015) of rs4147929. Subgroup analysis showed that the frequency of the rs4147929 A allele in male patients with PD was significantly higher than that in male controls (nominal P = 0.036). For the rs3752246 polymorphism, the frequency of the G allele was significantly higher in patients with PD than in controls, and the dominant model fit the data best when considering the nominal P-values (nominal P = 0.019, nominal P = 0.033, respectively). Differences in G allele and genotypes frequencies between patients and controls remained significant in women (nominal P = 0.032 for allele, nominal P = 0.015 for genotype), as well as in individuals aged more than 50 years (nominal P = 0.044, nominal P = 0.020, respectively). No significant differences were observed in allele or genotype frequencies between patients with PD and healthy controls for rs3764650. The frequency of the TCG (rs3764650–rs3752246–rs4147929) haplotype was significantly lower in the PD group than in the healthy control group (odds ratio = 0.772; 95% confidence interval = 0.634–0.940; P = 0.011). ConclusionThe rs4147929 polymorphism was significantly associated with PD susceptibility in the northern Chinese Han population. The A allele of rs4147929 was a risk factor for developing PD. The TCG haplotype presented a protective role in the pathogenesis of PD. Further studies using larger sample sizes, considering different clinical and biochemical parameters such as the cognitive status of subjects at the same time, are warranted to better clarify the effects of these common variants on the pathogenesis and development of PD.