Cell-specific overexpression of COMT in dopaminergic neurons of Parkinson's disease

Naoko Kuzumaki, Yukari Suda, Chizuru Iwasawa, Michiko Narita, Takefumi Sone, Moe Watanabe, Aya Maekawa, Takuya Matsumoto, Wado Akamatsu, Katsuhide Igarashi, Hideki Tamura, Hideyuki Takeshima, Vivianne L. Tawfik, Toshikazu Ushijima, Nobutaka Hattori, Hideyuki Okano, Minoru Narita

研究成果: Article査読

8 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1675-1689
ページ数15
ジャーナルBrain
142
6
DOI
出版ステータスPublished - 2019 6月 1

ASJC Scopus subject areas

  • 臨床神経学

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