期刊
NEUROBIOLOGY OF AGING
卷 107, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2021.06.011
关键词
Parkinson's disease; RAB35; promoter; SNP; rs17525453; TFII-I; Transcriptional activity
资金
- Ministry of Science and Technology, Taiwan [MOST107-2320-B-182-036-MY3, MOST109-2314-B-182A-072-MY3]
- Chang Gung Memorial Hospital, Taiwan [CMRPD1H0283, CMRPG3K09512, CMRPG3J0761-3]
- Healthy Aging Research Center, Chang Gung University, Taiwan [EMRPD1H0551, EMRPD1H0381, EMRPD1K0481, EMRPD1K0361]
The upregulation of RAB35 in Parkinson's disease is likely caused by the SNP rs17525453 in the RAB35 gene promoter. This SNP is associated with an increased risk of idiopathic PD, with the C allele frequency higher in sporadic PD patients. The CC and CT genotypes significantly elevate the risk of PD compared to the TT genotype, suggesting a potential genetic susceptibility factor for PD development.
Our previous study suggests that upregulated RAB35 is implicated in etiology of Parkinson's disease (PD). We hypothesized that upregulated RAB35 results from single nucleotide polymorphisms (SNPs) in RAB35 gene promoter. We identified SNPs within RAB35 gene promoter by analyzing DNA samples of discovery cohort and validation cohort. SNP rs17525453 within RAB35 gene promoter (T > C at position of -66) was significantly associated with idiopathic PD patients. Compared to normal controls, sporadic PD patients had higher C allele frequency. CC and CT genotype significantly increased risk of PD compared with TT genotype. SNP rs17525453 within RAB35 gene promoter leads to formation of transcription factor TFII-I binding site. Results of EMSA and supershift assay indicated that TFII-I binds to rs17525453 sequence of RAB35 gene promoter. Luciferase reporter assays showed that rs17525453 variant of RAB35 gene promoter possesses an augmented transcriptional activity. Our results suggest that functional variant rs17525453 within RAB35 gene promoter is likely to enhance transcriptional activity and upregulate RAB35 protein, which could lead to increased risk of PD in Taiwanese population. (C) 2021 Elsevier Inc. All rights reserved.
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