scholarly journals Enrichment of Rare Variants in E3 Ubiquitin Ligase Genes in Early Onset Parkinson’s Disease

2021 ◽  
Author(s):  
Xiaojing Gu ◽  
Yanbing Hou ◽  
Yongping Chen ◽  
Ruwei Ou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Early Onset ◽  
Rare Variants ◽  
E3 Ubiquitin Ligase ◽  
Whole Exome ◽  
Significant Enrichment ◽  
Aggregate Burden ◽  
Early Onset Parkinson’S Disease

Abstract BackgroundDysfunction of the ubiquitination proteasome system (UPS) is important in the pathogenesis of Parkinson’s disease (PD). Patients with early onset PD (EOPD) are more susceptible to genetic factors. We systematically examined the overlaps between E3 ubiquitin ligase genes and EOPD. MethodsA total of 695 EOPD patients were sequenced with whole exome sequencing. Aggregate burden for rare variants (Minor allele frequency <0.001 and <0.0001) in a total of 44 E3 ubiquitin ligase genes causing disorders involved in the nervous system were analyzed.ResultsThere was significant enrichment of the rare and rare damaging variants in the E3 ubiquitin ligase genes in EOPD patients. Detailly, at the gene-based level, the strongest associations were found in HERC1, IRF2BPL, KMT2D, RAPSN, RLIM, RNF168 and RNF216. ConclusionOur findings highlight the importance of the UPS mechanism in the pathogenesis of PD from the genetic perspective. Moreover, our study also expanded the susceptible gene spectrum for PD.

scholarly journals The Landscape of Parkin Variants Reveals Pathogenic Mechanisms and Therapeutic Targets in Parkinson’s Disease

2018 ◽  
Author(s):  
Wei Yi ◽  
Emma J. MacDougall ◽  
Matthew Y. Tang ◽  
Andrea I. Krahn ◽  
Ziv Gan-Or ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Specific Drug ◽  
Common Cause ◽  
Naturally Occurring ◽  
Population Databases ◽  
Early Onset Parkinson’S Disease

AbstractMutations in Parkin (PARK2), which encodes an E3 ubiquitin ligase implicated in mitophagy, are the most common cause of early onset Parkinson’s Disease (PD). Hundreds of naturally occurring Parkin variants have been reported, both in PD patient and population databases. However, the effects of the majority of these variants on the function of Parkin and in PD pathogenesis remains unknown. Here we develop a framework for classification of the pathogenicity of Parkin variants based on the integration of clinical and functional evidence – including measures of mitophagy and protein stability, and predictive structural modeling – and assess 51 naturally occurring Parkin variants accordingly. Surprisingly, only a minority of Parkin variants, even among those previously associated with PD, disrupted Parkin function. Moreover, a few of these naturally occurring Parkin variants actually enhanced mitophagy. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally-occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. Together, the findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets to stratify patients for genotype-specific drug design.

scholarly journals Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

2020 ◽  
Author(s):  
Bernabe I. Bustos ◽  
Dimitri Krainc ◽  
Steven J. Lubbe ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Genetic Component ◽  
Genetic Risk Assessment ◽  
Whole Exome

ABSTRACTParkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a “hypothesis-free” exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95×10−26, beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease- and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.

Rare Variants Analysis of Lysosomal Related Genes in Early-Onset and Familial Parkinson’s Disease in a Chinese Cohort

2021 ◽  
pp. 1-11
Author(s):  
Yong-Ping Chen ◽  
Xiao-Jing Gu ◽  
Wei Song ◽  
Yan-Bing Hou ◽  
Ru-Wei Ou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Rare Variants ◽  
Lysosomal Storage ◽  
Asian Populations ◽  
Whole Exome ◽  
Gene Level ◽  
Chinese Cohort

Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson’s disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence.

scholarly journals Whole exome sequencing identified a new compound heterozygous PRKN mutation in a Chinese family with early-onset Parkinson’s disease

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Tianbai Li ◽  
Daqing Kou ◽  
Yanhua Cui ◽  
Weidong Le
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Early Onset ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Therapy Strategy ◽  
Whole Exome ◽  
Early Onset Parkinson’S Disease

Abstract Early-onset Parkinson’s disease (EOPD) is usually caused by genetic variants and patients with EOPD develop symptoms before the age of 50, accounting for 5% Parkinson’s disease (PD). Here we present a Chinese Han pedigree with clinical features of EOPD. To determine the diagnosis and pathogenic mutations of this pedigree, whole exome sequencing, Sanger sequencing and real-time quantitative PCR were performed to detect all the four family members. Our results showed that a new form of compound heterozygous mutation in the PRKN gene, consisting of heterozygous point mutation c.850G &gt; C (p.G284R) along with exon 4 deletion, is the causative genetic factor for EOPD in this pedigree. These discoveries may have implications for genetic counseling, clinical management and developing PRKN target gene therapy strategy.

Whole-exome sequencing in early-onset Parkinson's disease among ethnic Chinese

2020 ◽  
Vol 90 ◽  
pp. 150.e5-150.e11 ◽  
Author(s):  
Nannan Li ◽  
Ling Wang ◽  
Jinhong Zhang ◽  
Eng-King Tan ◽  
Junying Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Early Onset ◽  
Ethnic Chinese ◽  
Whole Exome ◽  
Early Onset Parkinson’S Disease

scholarly journals The landscape of Parkin variants reveals pathogenic mechanisms and therapeutic targets in Parkinson’s disease

2019 ◽  
Vol 28 (17) ◽  
pp. 2811-2825 ◽  
Author(s):  
Wei Yi ◽  
Emma J MacDougall ◽  
Matthew Y Tang ◽  
Andrea I Krahn ◽  
Ziv Gan-Or ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Specific Drug ◽  
Common Cause ◽  
Naturally Occurring ◽  
Population Databases ◽  
Early Onset Parkinson’S Disease

Abstract Mutations in Parkin (PARK2), which encodes an E3 ubiquitin ligase implicated in mitophagy, are the most common cause of early-onset Parkinson’s disease (EOPD). Hundreds of naturally occurring Parkin variants have been reported, both in Parkinson's disease (PD) patient and population databases. However, the effects of the majority of these variants on the function of Parkin and in PD pathogenesis remain unknown. Here we develop a framework for classification of the pathogenicity of Parkin variants based on the integration of clinical and functional evidence—including measures of mitophagy and protein stability and predictive structural modeling—and assess 51 naturally occurring Parkin variants accordingly. Surprisingly, only a minority of Parkin variants, even among those previously associated with PD, disrupted Parkin function. Moreover, a few of these naturally occurring Parkin variants actually enhanced mitophagy. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. Together, the findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets to stratify patients for genotype-specific drug design.

Switching on ubiquitylation by phosphorylating a ubiquitous activator

2014 ◽  
Vol 460 (3) ◽  
pp. e1-e3 ◽  
Author(s):  
Gary S. Shaw
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Mitochondrial Protein ◽  
E3 Ubiquitin Ligase ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Depolarization ◽  
Biochemical Journal ◽  
Phosphatase And Tensin Homologue ◽  
Early Onset Parkinson’S Disease

The dysfunction of the E3 ubiquitin ligase Parkin is a key contributor to the development of early-onset Parkinson's disease. Parkin is responsible for the labelling of outer mitochondrial membrane proteins with the small modifier protein ubiquitin in response to oxidative stress. This ubiquitylation signals the clearance of the damaged mitochondria to preserve overall cell health. Recent structural and biochemical experiments have shown that native Parkin exists in an autoinhibited state that must be activated in order to unmask its full ubiquitylation potential. In a recent article in the Biochemical Journal (vol. 460, pp. 127–139), Kazlauskaite and co-workers identified that the Parkinson's disease-associated kinase PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced putative kinase 1] can phosphorylate ubiquitin in response to mitochondrial depolarization. Furthermore, the authors demonstrated that phosphorylated ubiquitin can activate Parkin's E3 ligase activity and promote both increased autoubiquitylation and substrate ubiquitylation of the mitochondrial protein Miro1. The study provides exciting initial insights that show how PINK1 might activate ubiquitin through phosphorylation, and how this important regulatory step might switch on Parkin-mediated ubiquitylation.

„Early Onset Parkinson's Disease“: Korrelation zwischen Alter bei Krankheitsbeginn und Verlauf?

2005 ◽  
Vol 32 (S 1) ◽  
Author(s):  
A Janzen ◽  
B Winner ◽  
M Lange ◽  
Z Kohl ◽  
K Pfeifer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Early Onset Parkinson’S Disease
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