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Mitochondrial DNA variants as genetic risk factors for Parkinson disease

Authors :
Jiin-Haur Chuang
Jung-Fu Chen
Wen-Chin Lee
Chin-Song Lu
Chia-Wei Liou
Pei-Wen Wang
Mao-Meng Tiao
Sheng-Teng Huang
Shang-Der Chen
Rou-Shayn Chen
T. L. Huang
P. H. Huang
Tsu-Kung Lin
Shao-Wen Weng
Source :
European Journal of Neurology. 23:1289-1300
Publication Year :
2016
Publisher :
Wiley, 2016.

Abstract

Background and purpose Investigation of the relationship between mitochondrial DNA (mtDNA) variants and Parkinson disease (PD) remains an issue awaiting more supportive evidence. Moreover, an affirming cellular model study is also lacking. Methods The index mtDNA variants and their defining mitochondrial haplogroup were determined in 725 PD patients and 744 non-PD controls. Full-length mtDNA sequences were also conducted in 110 cases harboring various haplogroups. Cybrid cellular models, composed by fusion of mitochondria-depleted rho-zero cells and donor mitochondria, were used for a rotenone-induced PD simulation study. Results Multivariate logistic regression analysis revealed that subjects harboring the mitochondrial haplogroup B5 have resistance against PD (odds ratio 0.50, 95% confidence interval 0.32–0.78; P = 0.002). Furthermore, a composite mtDNA variant group consisting of A10398G and G8584A at the coding region was found to have resistance against PD (odds ratio 0.50, 95% confidence interval 0.33–0.78; P = 0.001). In cellular studies, B4 and B5 cybrids were selected according to their higher resistance to rotenone, in comparison with cybrids harboring other haplogroups. The B5 cybrid, containing G8584A/A10398G variants, showed more resistance to rotenone than the B4 cybrid not harboring these variants. This is supported by findings of low reactive oxygen species generation and a low apoptosis rate in the B5 cybrid, whereas a higher expression of autophagy was observed in the B4 cybrid particularly under medium dosage and longer treatment time with rotenone. Conclusions Our studies, offering positive results from clinical investigations and cybrid experiments, provide data supporting the role of variant mtDNA in the risk of PD.

Details

ISSN :
13515101
Volume :
23
Database :
OpenAIRE
Journal :
European Journal of Neurology
Accession number :
edsair.doi.dedup.....c42417874cd16794b648b758bb0d61f6
Full Text :
https://doi.org/10.1111/ene.13020