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Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson's disease through mitochondrial dysfunction.
Kao, Chung-Yang; Xu, Mafei; Wang, Leiming; Lin, Shih-Chieh; Lee, Hui-Ju; Duraine, Lita; Bellen, Hugo J; Goldstein, David S; Tsai, Sophia Y; Tsai, Ming-Jer.
Afiliación
  • Kao CY; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
  • Xu M; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
  • Wang L; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
  • Lin SC; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • Lee HJ; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • Duraine L; Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • Bellen HJ; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
  • Goldstein DS; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
  • Tsai SY; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, United States of America.
  • Tsai MJ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS Genet ; 16(6): e1008868, 2020 06.
Article en En | MEDLINE | ID: mdl-32579581
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Factor de Transcripción COUP II / Neuronas Dopaminérgicas / Mitocondrias Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Factor de Transcripción COUP II / Neuronas Dopaminérgicas / Mitocondrias Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos