S18Y in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) associated with decreased risk of Parkinson's disease in Sweden

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Abstract

Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that removes ubiquitin from the C-terminal end of substrates and a component of the ubiquitin–proteasome system. A protective effect of a UCH-L1 variant, S18Y, was suggested since the common variant was found to be inversely associated with sporadic Parkinson's disease (PD). We investigated the association of S18Y in our Swedish PD material. The tyrosine variant was significantly inversely associated with PD (P=0.049) and with a low age of onset (⩽50 years) (P=0.017) in the case–control material, supporting the hypothesis of a protective function.

Introduction

Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), also known as PGP 9.5, is a neuron-specific enzyme and one of the most abundant proteins in the brain, comprising up to 1–2% of the total soluble brain protein [1], [2], [3]. The main function of UCH-L1 is to hydrolyse ubiquitin from the C-terminal end of substrates thus being a component of the ubiquitin–proteasome system [3], [4]. Immunoreactivity for UCH-L1 was detected in the eosinophilic cytoplasmic Lewy bodies within the remaining dopamine cells in substantia nigra in neurodegenerative disease [5]. Deletion of UCH-L1 in mice causes gracile axonal dystrophy (gad), a neurodegenerative disease, but gad-mice do not develop a Parkinsonian phenotype [6], [7]. The UCH-L1 involvement in protein degradation, its abundance in human brain and, particularly, its presence in Lewy bodies nevertheless suggests it may also play a role in Parkinson's disease (PD) pathogenesis. Such a role was shown when Leroy et al. [8] found a missense mutation in UCH-L1, located on chromosome 4p14, in an autosomal dominant PD family, defining the PARK5 locus. The first identified PD variant in UCH-L1, I93 M in exon 4, causes a partial loss of hydrolytic function [8]. Setsuie et al. [9] recently found dopaminergic neuronal loss in transgenic mice expressing the I93 M mutant. A protective effect of an UCH-L1 variant has also been suggested since the common S18Y polymorphism in UCH-L1 was found to be inversely associated with sporadic PD [10]. Furthermore, this was confirmed in a collaborative-pooled analysis including 970 cases and 2224 unrelated controls from 11 sites [11]. However, negative association studies of S18Y in PD have also been reported [12]. A recent large study by Healy et al. [13], which also used the haplotype-tagging approach, detected no association with PD.

In vitro studies show that UCH-L1 exerts two opposing enzymatic activities that affect α-synuclein degradation [14]. As a monomer, UCH-L1 hydrolyses poly-ubiquitin chains, which promotes the ubiquitination and proteasomal degradation of α-synuclein [14]. As a dimer, UCH-L1 ligates ubiquitin to α-synuclein via a K63 linkage which spares it from proteasomal degradation. The S18Y variant encodes a protein that is unable to dimerize and, therefore, favors degradation of α-synuclein. The S18Y variant causes a dramatic reduction of ubiquityl ligase activity in vitro, but no change of hydrolase activity [14]. We investigated the occurrence of the S18Y variant of UCH-L1 in a Swedish case–control PD material and whether S18Y had an effect on early age of onset. The I93 M mutation of UCH-L1 has so far only been found in the German autosomal dominant PD family and not in any sporadic PD cases and was therefore investigated in our Swedish PD cases with reported family history [8], [10].

Section snippets

Subjects

Our patient material was obtained after informed consent and approval of the local ethics committee; KI forskningsetikkommitté Nord and Forskningsetikkommittén, Göteborg University. All subjects were unrelated and of Caucasian origin. A total of 296 PD patients were recruited: 194 from Karolinska University Hospital, Stockholm and 102 from Sahlgrenska Hospital, Göteborg (mean age 68 years; mean age of onset 60 years). Control subjects were 235 healthy volunteers from Stockholm and Göteborg

Results

The S18Y variant was genotyped in 296 Swedish PD patients and 235 Swedish controls to determine the distribution of the S18Y variant in UCH-L1. The allele frequencies of S18Y in the Swedish case control material are summarized in Table 1. Genotype distributions among patients and controls were found to be in Hardy–Weinberg equilibrium. We assumed a similar effect in our Swedish PD material, compared to earlier reports, which allowed a one-sided test. There was a significant difference between

Discussion

Using the χ2 test and a one-sided P-value, we have confirmed an inverse association between the S18Y polymorphism of the UCH-L1 gene and PD, as previously reported by several groups in populations of different ethnic origin [11]. We also found that presence of the Y-allele protected against PD of “early” (below 50) rather than later age of onset PD, supporting observations in a French PD population [17]. We found the Y-allele frequency to be 17% in the control material which is in accordance

Conclusion

The main finding of Healy et al. [13] was that neither the S18Y variant nor other genetic variants in UCH-L1 influence PD risk in Caucasians, but they declare that a small protective effect cannot definitively be excluded. The UCH-L1 involvement in protein degradation, its abundance in human brain and its presence in Lewy bodies support the relevance for its involvement in PD pathogenesis. The in vitro studies which show that UCH-L1 exerts two opposing enzymatic activities that affect α

Acknowledgments

We thank Ann-Christin Thelander, Karin Lundströmer, Karin Pernold and Caroline Ran for excellent technical assistance. This study was supported by: the Swedish Research Council, the Swedish Brain Foundation, Hållstens Forskningsstiftelse, Björn Oscarssons Stiftelse, Åhlén's Foundation, The Swedish Parkinson Foundation, The Swedish Brain Power Initiative, Magnus Bergwalls Stiftelse, USPHS grants and Karolinska Institutet Funds.

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