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

doi:10.1093/brain/awz084

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

Department of Physiology

Research output: Contribution to journal › Article › peer-review

9 Citations (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 language	English
Pages (from-to)	1675-1689
Number of pages	15
Journal	Brain
Volume	142
Issue number	6
DOIs	https://doi.org/10.1093/brain/awz084
Publication status	Published - 2019 Jun 1

Keywords

COMT
Parkinson's disease
dopaminergic neuron
epigenetic modification
iPS

ASJC Scopus subject areas

Clinical Neurology

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10.1093/brain/awz084

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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, 142(6), 1675-1689. https://doi.org/10.1093/brain/awz084

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, VL, Ushijima, T, Hattori, N, Okano, H & Narita, M 2019, 'Cell-specific overexpression of COMT in dopaminergic neurons of Parkinson's disease', Brain, vol. 142, no. 6, pp. 1675-1689. https://doi.org/10.1093/brain/awz084

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title = "Cell-specific overexpression of COMT in dopaminergic neurons of Parkinson's disease",

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.",

keywords = "COMT, Parkinson's disease, dopaminergic neuron, epigenetic modification, iPS",

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

note = "Funding Information: This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP16K08280. This work was also supported by the Project for the Realization of Regenerative Medicine and Support for the Core Institutes for iPS cell research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) (JP25830055). Publisher Copyright: {\textcopyright} 2019 The Author(s).",

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AU - Kuzumaki, Naoko

AU - Suda, Yukari

AU - Iwasawa, Chizuru

AU - Narita, Michiko

AU - Sone, Takefumi

AU - Watanabe, Moe

AU - Maekawa, Aya

AU - Matsumoto, Takuya

AU - Akamatsu, Wado

AU - Igarashi, Katsuhide

AU - Tamura, Hideki

AU - Takeshima, Hideyuki

AU - Tawfik, Vivianne L.

AU - Ushijima, Toshikazu

AU - Hattori, Nobutaka

AU - Okano, Hideyuki

AU - Narita, Minoru

N1 - Funding Information: This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP16K08280. This work was also supported by the Project for the Realization of Regenerative Medicine and Support for the Core Institutes for iPS cell research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) (JP25830055). Publisher Copyright: © 2019 The Author(s).

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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