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Human Molecular Genetics, 2003, Vol. 12, No. 7 711-725
DOI: 10.1093/hmg/ddg084
© 2003 Oxford University Press

PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype

Tomohiro Okuda1,2, Hiroshi Hattori2, Sousuke Takeuchi3, Jun Shimizu3, Hiroko Ueda1, Jorma J. Palvimo4, Ichiro Kanazawa3,5, Hitoshi Kawano6, Masaya Nakagawa2 and Hitoshi Okazawa1,3,7,*

1Department of Molecular Therapeutics, Tokyo Metropolitan Institute for Neuroscience, 2-6, Musashi-dai, Fuchu, Tokyo 183-8526, Japan, 2Toyama Chemical Co., Ltd, 2-4-1, Shimo-Okui, Toyama 930-8508, Japan, 3Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, 4Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, FIN-00014 Helsinki, Finland, 5National Center for Neurology and Psychiatry, 4-1-1, Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan, 6Department of Developmental Morphology, Tokyo Metropolitan Institute for Neuroscience, 2-6, Musashi-dai, Fuchu, Tokyo 183-8526, Japan and 7PRESTO, Japan Science and Technology Corporation (JST), 4-1-8, Honmachi, Kawagoe, Saitama 332-0012, Japan

Received September 19, 2002; Accepted February 1, 2003

A body of experimental evidence indicates that transcription and/or mRNA processing factors interacting with the polyglutamine disease gene products play crucial roles in the pathology. PQBP-1 is one of these factors and it has been shown to interact with the spinocerebellar ataxia type-1 (SCA1) disease gene product, ataxin-1. Our previous data suggested that relatively high expression of PQBP-1 in the cerebellum might explain the selective neuronal degeneration of SCA1. To further test whether PQBP-1 expression level regulates neuronal death, we generated transgenic mice of human PQBP-1 driven by a regulatory element for ubiquitous gene expression. The mice showed a late-onset and gradually progressive motor neuron disease-like phenotype, which might be related to neurogenic muscular atrophy observed in SCA1 patients. Ataxia could not be discriminated from predominant progressive weakness. Pathological examinations of the transgenic mice revealed loss of Purkinje and granular cells in the cerebellum as well as that of spinal motor neurons, corresponding to the pathology of human SCA1. These findings show that excessive action of PQBP-1 causes neuronal dysfunction and support PQBP-1 being involved in the pathology of SCA1.

* To whom correspondence should be addressed. Tel: +81 423253881; Fax: +81 423218678; Email: okazawa-tky{at}umin.ac.jp or okazawa{at}tmin.ac.jp


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