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

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1675-1689
Number of pages15
JournalBrain : a journal of neurology
Volume142
Issue number6
DOIs
Publication statusPublished - 2019 Jun 1

Keywords

  • COMT
  • dopaminergic neuron
  • epigenetic modification
  • iPS
  • Parkinson’s disease

ASJC Scopus subject areas

  • Clinical Neurology

Fingerprint Dive into the research topics of 'Cell-specific overexpression of COMT in dopaminergic neurons of Parkinson's disease'. Together they form a unique fingerprint.

  • Cite this

    Kuzumaki, N., Suda, Y., Iwasawa, C., Narita, M., Sone, T., Watanabe, M., Maekawa, A., Matsumoto, T., Akamatsu, W., Igarashi, K., Tamura, H., Takeshima, H., Tawfik, V. L., Ushijima, T., Hattori, N., Okano, H., & Narita, M. (2019). Cell-specific overexpression of COMT in dopaminergic neurons of Parkinson's disease. Brain : a journal of neurology, 142(6), 1675-1689. https://doi.org/10.1093/brain/awz084