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
Source: PubMed


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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    • "Furthermore, it is interesting that this gene with another missense mutation, S18Y, is protective against PD [52]. 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 [53]. 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) [21], PTEN-induced putative kinase 1 (PINK1, PARK6) [24], DJ-1 (PARK7) [25] [26], and ATP13A2 (PARK9) [30] [31]. "
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    • "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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    Frontiers in Molecular Neuroscience 11/2013; 6:40. DOI:10.3389/fnmol.2013.00040 · 4.08 Impact Factor
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    • "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 [8], [13], [14]. However, more recent studies have failed to find significant association between S18Y polymorphism and reduced PD risk [15], [16]. "
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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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