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A polymorphic variation of serine to tyrosine at codon 18 in the ubiquitin C-terminal hydrolase-L1 gene is associated with a reduced risk of sporadic Parkinson's disease in a Japanese population

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Abstract

Recent studies suggest that ubiquitin C-terminal hydrolase-L1 (UCH-L1), a neuronal deubiquitinating enzyme, represents a candidate gene responsible for either the development of familial Parkinson’s disease (PD) or the protection against sporadic PD in Caucasian populations, although these findings are not fully verified in non-Caucasian populations. To determine an association of the variations in the UCH-L1 gene with development of sporadic PD in a Japanese population, a Ser18Tyr polymorphism and an Ile93Met mutation were studied by PCR-RFLP analysis in 74 Japanese patients with sporadic PD and 155 age-matched non-PD controls. The frequency of 18Tyr allele was significantly lower in PD patients than the controls (38.5% vs. 53.5%) (χ2=9.064, p=0.0026; the odds ratio=1.84, 95% confident interval=1.23–2.74). Furthermore, the frequency of 18Tyr/Tyr homozygotes was significantly lower in PD patients than the controls (14.9% vs. 33.5%), compared with that of two other genotypes combined (χ2=8.767, p=0.0031; the odds ratio=0.35, 95% confident interval=0.27–0.45). The Ile93Met substitution was not detected in any Japanese subjects examined. These results indicate that the presence of 18Tyr allele and 18Tyr/Tyr homozygosity in the UCH-L1 gene is associated with a reduced risk for development of sporadic PD in a Japanese population, supporting the previous observations on sporadic PD in Caucasian populations.

Introduction

Parkinson's disease (PD) is supposed to be caused by a combination of multiple genetic and environmental factors [1], [2]. Recently, two missense mutations in the α-synuclein gene (PARK1) on chromosome 4q21–22 are identified in a small number of the patients with autosomal dominant form of PD in Italian and German families, while a battery of deletional or point mutations in the parkin gene (PARK2) on chromosome 6q25.2–27 is found in larger numbers of the patients with autosomal recessive form of juvenile parkinsonism (AR-JP) in Japanese and Caucasian families [1], [2]. At present, the genetic factors contributing to susceptibility to non-hereditary idiopathic PD, which constitutes the great majority of PD cases, remain to be elucidated [1], [2]. To identify the genetic factors responsible for the development of sporadic PD, a number of genetic association studies have focused on screening of the genes involved in the regulation of the catecholaminergic neurotransmitter metabolism and production of neurotoxins; however, most of these studies have failed to find out specific genetic determinants, except for several inconsistent observations, possibly derived from the differences in the allele frequencies among distinct ethnic backgrounds [3].

The ubiquitin–proteasome system plays a key role in cell-cycle progression, signal transduction, transcriptional regulation, DNA repair, stress response, programmed cell death, and antigen presentation [4]. Increasing evidence indicates that dysfunction of the ubiquitin-dependent proteolytic system contributes to progressive accumulation of neuronal and glial inclusions composed of ubiquitinated protein aggregates in various neurodegenerative diseases [5]. Lewy bodies, a pathological hallmark of PD and dementia with Lewy bodies, contain ubiquitin, ubiquitin C-terminal hydrolase-L1 (UCH-L1) and proteasome subunits [6]. UCH-L1, alternatively designated protein gene product 9.5 (PGP9.5), is a deubiquitinating enzyme which hydrolyzes small adducts of ubiquitin and generate free monomeric ubiquitin from ubiquitin proproteins, and it is expressed predominantly in neurons and neuroendocrine cells with its location in the cytoplasm [7]. The gracile axonal dystrophy (gad) mouse is an autosomal recessive mutant showing ataxia, pathologically characterized by dying-back type axonal degeneration and accumulation of ubiquitinated deposits along the sensory and motor nervous systems [8]. The gad-causing mutation is an in-frame deletion including exons 7 and 8 of the UCH-L1 gene, resulting in the production of a truncated UCH-L1 protein lacking the catalytic segment [8]. These observations suggest that a malfunction of UCH-L1 might accelerate the formation of ubiquitinated protein inclusions that disrupt cellular homeostasis in neural cells. Therefore, UCH-L1 represents an ideal candidate gene for PD.

A recent study has identified an isoleucine (Ile) to methionine (Met) substitution at codon 93 in exon 4 of the UCH-L1 gene in two PD patients of a German family, suggesting that development of PD is closely associated with a reduced UCH-L1 activity [9]. However, following studies performed in larger numbers of the patients with familial PD of the diverse ethnic origins including Japanese subjects have failed to identify the Ile93Met substitution, indicating that it is not a major mutation causing familial PD [10], [11], [12], [13]. Several studies have shown that a serine (Ser) to tyrosine (Tyr) polymorphism at codon 18 in exon 3 of the UCH-L1 gene exhibits a protective effect against the development of sporadic PD in American and German populations [12], [14], whereas these observations are not verified in an Australian population [15]. These inconsistent results might be attributable to the differences in the prevalence of a particular allele among distinct ethnic populations, the validity of clinical diagnosis of PD, or the control subjects examined [3].

The aim of the present study is to determine an association of Ser18Tyr variation in the UCH-L1 gene with the development of sporadic PD in a Japanese population.

Section snippets

Study population

The study population consisted of 74 patients with sporadic PD (28 men and 46 women, age 46 to 86 years with the mean of 69.0±8.8 years), and 155 control subjects (79 men and 76 women, age 40 to 88 years with the mean of 66.4±11.8 years). The controls were randomly selected from the patients who had visited the neurologic clinic of Saga Medical School Hospital and were diagnosed as not having PD by neurologists. All PD patients and controls were genetically unrelated Japanese who resided in the

Results

By PCR-RFLP analysis, the Ser18Tyr substitution located in exon 3 was identified in both study populations, while the Ile93Met substitution located in exon 4 was not detected in any subjects examined (n=229) (Table 1 and Fig. 1). The frequency of 18Tyr allele was significantly lower in PD patients than the controls (38.5% vs. 53.5%) (χ2=9.064, p=0.0026; the odds ratio=1.84, 95% confident interval=1.23–2.74) (Table 1). The frequency of 18Ser/Ser, 18Ser/Tyr or 18Tyr/Tyr genotype was 37.8%, 47.3%

Discussion

The present study has shown that the presence of 18Tyr allele and 18Tyr/Tyr homozygosity in the UCH-L1 gene is associated with a reduced risk of development of sporadic PD in a Japanese population, where the Ile93Met substitution was not detected in any Japanese sporadic PD and non-PD subjects examined, indicating that the absence of 18Tyr allele in the UCH-L1 gene does not represent a linkage disequilibrium with the Ile93Met substitution in the same gene. These observations are well consistent

Acknowledgements

This study was supported in part by a grant to J.-I.S. from the Symposium on Catecholamine Neurological Disorders, Sumitomo Pharmaceutical, Japan.

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