Ubiquitin specific proteases USP24 and USP40 and ubiquitin thiolesterase UCHL1 polymorphisms have synergic effect on the risk of Parkinson's disease among Taiwanese

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Abstract

Background

Impaired ubiquitin–proteasome system function may contribute to the pathogenesis of Parkinson's disease (PD).

Methods

We conducted a case–control study in a cohort of 517 PD cases and 518 ethnically matched controls to investigate the association of ubiquitin specific proteases USP24 rs487230 C>T, USP40 rs1048603 C>T, and ubiquitin thiolesterase UCHL1 rs5030732 A>C polymorphisms with the risk of PD.

Results

No significant difference in the genotype or allele distribution was found between PD and controls. After stratification by age, the genotype and allele frequencies of USP24 rs487230 are significantly different between PD and controls ≥ 60 years of age (P = 0.035 and 0.013, respectively). Multivariable logistic regression with adjusting for onset age and sex showed that, in a dominant model, USP24 T-carrying genotype was associated with risk reduction in developing PD in individuals ≥ 60 years of age (OR = 0.61; 95% CI = 0.41–0.90, P = 0.010). This is also true for T allele (OR = 0.64; 95% CI = 0.44–0.91, P = 0.023). When examining the interaction between genes on PD risk without age stratification, the protective effect of USP24 CT/TT genotype on PD risks was strengthened by the USP40 T-carrying genotype (OR = 0.42; 95% CI = 0.22–0.81, P = 0.009) and UCHL1 C-carrying genotype (OR = 0.67; 95% CI = 0.47–0.97, P = 0.032).

Conclusions

Our results suggest that USP24 alone plays a role in PD susceptibility among Taiwanese people ≥ 60 years of age, or acting synergistically with USP40 and UCHL1 in the total subjects.

Introduction

Parkinson's disease (PD) is the second common neurodegenerative disorder caused by progressive and selective loss of dopamine neurons in the substantia nigra (SNc). Clinically PD is characterized by rest tremor, rigidity, bradykinesia and postural instability. Pathologically it is defined by the presence of Lewy bodies, intracellular neuronal inclusions in the SNc and at other sites of the brain [1]. The etiology of PD remains elusive. An interaction between genetic and environmental factors is thought to contribute to the development of the disease [2]. Causal mutations in genes of α-synuclein (PARK1), parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7), LRRK2 (PARK8), and ATP13A2 (PARK9) have been identified [3], indicating that dysregulation of protein processing pathway and impairment of mitochondrial function may contribute to the pathogenesis of PD.

The ubiquitin–proteasome system (UPS) is an important pathway that controls the degradation of unwanted intracellular proteins in eukaryocytic cells [4]. Impaired UPS function is likely to be involved in the pathogenesis of PD and other neurodegenerative diseases [5]. Ubiquitin thiolesterase UCHL1 was first discovered as a member of the ubiquitin carboxy-terminal hydrolase family of deubiquitinating enzymes [6]. It also functions as an ubiquitin ligase [7] and a mono-ubiquitin stabilizer [8]. A missense mutation (I93M) in a German PD family was the first evidence that UCHL1 has implication on PD [9]. Reduced UCHL1 protein expression has been reported in PD [10]. A polymorphism S18Y in UCHL1 was linked to decreased susceptibility to PD in some studies [11], [12], [13], but which was not confirmed in others [14], [15], [16].

Recently genetic studies have defined that two additional loci, PARK10 and PARK11, may play a role in conferring risk to, or affecting age at onset (AAO) of PD [17], [18], [19]. Within PARK10 and PARK11 loci, ubiquitin specific proteases USP24 and USP40 have a strong biological plausibility to be involved in PD. Both USPs belonged to the ubiquitin-conjugating and deubiquitinating families [20]. More recently multiple disease-associated single nucleotide polymorphisms (SNPs) of USP24 and USP40 were identified in a case–control study [21]. Among them, USP24 rs487230 C>T (p.Ala2385Val) and USP40 rs1048603 C>T (p.Arg1123Cys) polymorphisms were significantly associated with the disease risk (P = 0.0012 and 0.0067, respectively).

Given that USP24, USP40 and UCHL1 are all involved in the cellular clearance of abnormal proteins and UPS as a causal pathway in PD, we aimed to evaluate the impact of these genes and their interactions on the development of sporadic PD in Taiwan. We performed polymorphism analysis of USP24, USP40 and UCHL1 in a large sample of patients and controls.

Section snippets

Subjects

Five hundred and seventeen patients with probable PD (43.7% female) were included, AAO 19–86 years (mean: 62.7 ± 11.3 years), from the neurology clinic of Chang-Gung Memorial hospital. All patients were diagnosed according to the published criteria [22]. They exhibit at least 2 of the 4 cardinal signs of PD: rest tremor, cogwheel rigidity, bradykinesia or postural-reflex impairment. Exclusion criteria include prior history of multiple cerebrovascular events or other causes of parkinsonian symptoms

Results

The genotype and allele frequency distributions of the USP24 rs487230, USP40 rs1048603 and UCHL1 rs5030732 polymorphisms in PD patients and controls are displayed in Table 2 (part of UCHL1 data has been published in [16]). The allele and genotype distributions in PD and controls did not deviate significantly from Hardy–Weinberg equilibrium for all the polymorphisms examined. There was no significant difference between two groups in each SNP analyzed. Since age is a major risk factor for PD, we

Discussion

UPS pathway is well-known to be involved in the etiology of PD, as intraneuronal inclusions with ubiquitinated proteins and components of the UPS are key pathological features of the disease [5]. Being a multigenic disorder of the UPS [25], difference in the gradual decrease of UPS efficiency as we age may influence individuals' PD susceptibility. To examine this, 2 missense SNPs in USP24 and USP40 which previously showed significant association with PD risk [21] were analyzed. Additionally,

Acknowledgements

The authors thank the PD patients and normal controls for participating in this study. All experiments were approved by the hospital internal ethics and scientific boards. This work was supported by grant NSC96-2314-B-182A-099-MY2 from the National Science Council, Executive Yuan.

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