Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson’s disease through mitochondrial dysfunction

English version

Autoři: Chung-Yang Kao ^aff001; Mafei Xu ^aff001; Leiming Wang ^aff001; Shih-Chieh Lin ^aff002; Hui-Ju Lee ^aff001; Lita Duraine ^aff005; Hugo J. Bellen ^aff005; David S. Goldstein ^aff010; Sophia Y. Tsai ^aff001; Ming-Jer Tsai ^aff001
Působiště autorů: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America ^aff001; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan ^aff002; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan ^aff003; Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan ^aff004; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America ^aff005; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, United States of America ^aff006; Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America ^aff007; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America ^aff008; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America ^aff009; Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America ^aff010
Vyšlo v časopise: Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson’s disease through mitochondrial dysfunction. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008868
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008868

Souhrn

Parkinson’s disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target.

Klíčová slova:

DNA methylation – Dopamine – Midbrain – Mitochondria – Mouse models – Neostriatum – Neurons – Parkinson disease

Zdroje

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