Cell-specific overexpression of COMT in dopaminergic neurons of Parkinson’s disease
| Autor: | Vivianne L. Tawfik, Wado Akamatsu, Toshikazu Ushijima, Takefumi Sone, Chizuru Iwasawa, Naoko Kuzumaki, Hideyuki Okano, Aya Maekawa, Hideyuki Takeshima, Katsuhide Igarashi, Hideki Tamura, Moe Watanabe, Michiko Narita, Minoru Narita, Takuya Matsumoto, Nobutaka Hattori, Yukari Suda |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Parkinson's disease Ubiquitin-Protein Ligases Induced Pluripotent Stem Cells Mice Transgenic Substantia nigra Gene mutation Catechol O-Methyltransferase Parkin 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Induced pluripotent stem cell Dopamine transporter Dopamine Plasma Membrane Transport Proteins Catechol-O-methyl transferase biology Dopaminergic Neurons Dopaminergic Parkinson Disease medicine.disease Substantia Nigra 030104 developmental biology nervous system biology.protein Neurology (clinical) Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Brain. 142:1675-1689 |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awz084 |
| Popis: | The mechanism by which dopaminergic neurons are selectively affected in Parkinson's disease is not fully understood. In this study, we found a dramatic increase in the expression of catechol-O-methyltransferase (COMT), along with a lower level of DNA methylation, in induced pluripotent stem cell-derived dopaminergic neurons from patients with parkin (PARK2) gene mutations compared to those from healthy controls. In addition, a significant increase in the expression of COMT was found in dopaminergic neurons of isogenic PARK2 induced pluripotent stem cell lines that mimicked loss of function of PARK2 by CRISPR Cas9 technology. In dopamine transporter (DAT)-Cre mice, overexpression of COMT, specifically in dopaminergic neurons of the substantia nigra, produced cataleptic behaviours associated with impaired motor coordination. These findings suggest that upregulation of COMT, likely resulting from DNA hypomethylation, in dopaminergic neurons may contribute to the initial stage of neuronal dysfunction in Parkinson's disease. |
| Databáze: | OpenAIRE |
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