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