Article

UCHL-1 is not a Parkinson's disease susceptibility gene

University of Cambridge, Cambridge, England, United Kingdom
Annals of Neurology (Impact Factor: 11.91). 04/2006; 59(4):627-33. DOI: 10.1002/ana.20757
Source: PubMed

ABSTRACT 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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    • "However, UCH-L1 as a causative factor has been controversial. The association between UCH-L1 mutation and PD could not be replicated in different populations in case–control study (Healy et al. 2006; Hutter et al. 2008; Zhang et al. 2008). Reduced UCH-L1 expression was also found in Alzheimer's disease (Lombardino et al. 2005; Xue and Jia 2006). "
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