Journal Article

Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-Jun NH<sub>2</sub>-terminal kinase

Yuko Okamura-Oho, Toshiyuki Miyashita, Kazuaki Nagao, Seigo Shima, Yukie Ogata, Toshiaki Katada, Hiroshi Nishina and Masao Yamada

in Human Molecular Genetics

Volume 12, issue 13, pages 1535-1542
Published in print July 2003 | ISSN: 0964-6906
Published online July 2003 | e-ISSN: 1460-2083 | DOI:
Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-Jun NH2-terminal kinase

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Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominant-inherited neurodegenerative disease characterized by selective cell loss in particular neuronal pathways. This is caused by expansion of CAG repeats in the coding region of the DRPLA gene, and the extended polyglutamine tract (polyQ) confers a toxic activity. It is valuable to characterize disease gene products for elucidation of the mechanism underlying neuron death at specific anatomical areas of the brain. Here, we define the DRPLA protein as a phosphoprotein, and c-Jun NH2-terminal kinase (JNK) is one of the major factors involved in its phosphorylation. Endogenous DRPLA protein was serine-phosphorylated. Phosphorylation was demonstrated in a recombinant JNK activation system in vitro and also in overexpressing cells by transfection after the JNK activation with osmotic pressure. One of the phospho-acceptor sites for JNK appearing in the DRPLA sequence was indeed phosphorylated, which was confirmed by a specific antibody raised against the phosphopeptide. Kinetic studies in the JNK recombinant system showed that expanded polyQ slightly reduced the affinity of JNK to the protein. Thus, the abnormal DRPLA protein seems to be slowly phosphorylated in a certain condition of JNK activation in patients. It may delay a process that is essential in keeping neurons alive.

Journal Article.  5929 words.  Illustrated.

Subjects: Genetics and Genomics

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