UCHL-1 is not a Parkinson's disease susceptibility gene
University of Cambridge, Cambridge, England, United Kingdom Annals of Neurology
(Impact Factor: 9.98).
04/2006; 59(4):627-33. DOI: 10.1002/ana.20757
The UCHL-1 gene is widely cited as a susceptibility factor for sporadic Parkinson's disease (PD). The strongest evidence comes from a meta-analysis of small studies that reported the S18Y polymorphism as protective against PD, after pooling studies of white and Asian subjects. Here, we present data that challenge this association.
In a new large case-control study in white individuals (3,023 subjects), the S18Y variant was not protective against PD under any genetic model of inheritance. Similarly, a more powerful haplotype-tagging approach did not detect other associated variants.
Finally, in an updated S18Y-PD meta-analysis (6,594 subjects), no significant association was observed under additive, recessive, or dominant models (odds ratio = 1.00 [95% confidence interval: 0.74-1.33]; odds ratio = 1.01 [95% confidence interval: 0.76-1.35]; and odds ratio = 0.96 [95% confidence interval: 0.86-1.08], respectively), and a cumulative meta-analysis showed a trend toward a null effect.
Based on the current evidence, the UCHL-1 gene does not exhibit a protective effect in PD.
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Available from: Masaaki Waragai
- "Furthermore, it is interesting that this gene with another missense mutation, S18Y, is protective against PD . Indeed, the role of PARK5 in the pathogenesis of PD is controversial since recent association studies have failed to show that UCHL1 is susceptible to PD . On the other hand, several gene products that are known to confer an autosomal-recessive trait in PD have been identified (Table 1), including parkin (PARK2) , PTEN-induced putative kinase 1 (PINK1, PARK6) , DJ-1 (PARK7)  , and ATP13A2 (PARK9)  . "
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ABSTRACT: Research on Parkinson's disease (PD) has made remarkable progress in recent decades, due largely to new genomic technologies, such as high throughput sequencing and microarray analyses. Since the discovery of a linkage of a missense mutation of the α-synuclein (αS) gene to a rare familial dominant form of PD in 1996, positional cloning and characterization of a number of familial PD risk factors have established a hypothesis that aggregation of αS may play a major role in the pathogenesis of PD. Furthermore, dozens of sensitizing alleles related to the disease have been identified by genome wide association studies (GWAS) and meta-GWAS, contributing to a better understanding of the pathological mechanisms of sporadic PD. Thus, the knowledge obtained from the association studies will be valuable for "the personal genome" of PD. Besides summarizing such progress, this paper focuses on the role of microRNAs in the field of PD research, since microRNAs might be promising as a biomarker and as a therapeutic reagent for PD. We further refer to a recent view that neurodegenerative diseases, including PD, coexist with metabolic disorders and are stimulated by type II diabetes, the most common disease among elderly populations. The development of genomic approaches may potentially contribute to therapeutic intervention for PD.
Available from: Mahendra Surendra Rao
- "Interestingly, patients with these mutations tend to display a loss of DA neurons, but no Lewy body accumulation, indicating that Parkin activity may be required for LB formation (Cook et al., 2012). It is worth noting that the controversial (Maraganore et al., 2004; Healy et al., 2006) "
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ABSTRACT: Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized primarily by the selective death of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain. Although several genetic forms of PD have been identified, the precise molecular mechanisms underlying DA neuron loss in PD remain elusive. In recent years, microRNAs (miRNAs) have been recognized as potent post-transcriptional regulators of gene expression with fundamental roles in numerous biological processes. Although their role in PD pathogenesis is still a very active area of investigation, several seminal studies have contributed significantly to our understanding of the roles these small non-coding RNAs play in the disease process. Among these are studies which have demonstrated specific miRNAs that target and down-regulate the expression of PD-related genes as well as those demonstrating a reciprocal relationship in which PD-related genes act to regulate miRNA processing machinery. Concurrently, a wealth of knowledge has become available regarding the molecular mechanisms that unify the underlying etiology of genetic and sporadic PD pathogenesis, including dysregulated protein quality control by the ubiquitin-proteasome system and autophagy pathway, activation of programmed cell death, mitochondrial damage and aberrant DA neurodevelopment and maintenance. Following a discussion of the interactions between PD-related genes and miRNAs, this review highlights those studies which have elucidated the roles of these pathways in PD pathogenesis. We highlight the potential of miRNAs to serve a critical regulatory role in the implicated disease pathways, given their capacity to modulate the expression of entire families of related genes. Although few studies have directly linked miRNA regulation of these pathways to PD, a strong foundation for investigation has been laid and this area holds promise to reveal novel therapeutic targets for PD.
Available from: Edward Rockenstein
- "Interestingly, a polymorphism in the UCH-L1 gene (S18Y), was found to be associated with a lower risk of developing PD, has a significantly reduced ligase activity leading to reduced levels of ubiquitinated a-syn , , . However, more recent studies have failed to find significant association between S18Y polymorphism and reduced PD risk , . "
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ABSTRACT: Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Abnormal accumulation and aggregation of alpha-synuclein (a-syn) within neurons, and mutations in the a-syn and UCH-L1 genes have been shown to play a role in the pathogenesis of PD. In light of recent reports suggesting an interaction between a-synuclein and UCH-L1, we investigated the effects of UCH-L1 inhibition on a-syn distribution and expression levels in primary neurons and hippocampal tissues derived from non transgenic (non tg) and a-syn over expressing tg mice. We show that suppression of UCH-L1 activity increased a-syn levels in control, non tg neurons, and resulted in a concomitant accumulation of presynaptic a-syn in these neurons. In contrast, blocking UCH-L1 activity in a-syn over expressing neurons decreased a-syn levels, and enhanced its synaptic clearance. In vitro studies verified the LDN-induced inhibition of UCH-L1 had minimal effect on LC3 (a marker of autophagy) in control cells, in cells over expressing a-syn UCH-L1 inhibition resulted in increased LC3 activity. These findings suggest a possible differential role of UCH-L1 function under normal and pathological conditions. Furthermore, in the context of a-syn-induced pathology, modulation of UCH-L1 activity could serve as a therapeutic tool to enhance the autophagy pathway and induce clearance of the observed accumulated/aggregated a-syn species in the PD brain.
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