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Human Molecular Genetics Advance Access originally published online on August 4, 2004
Human Molecular Genetics 2004 13(19):2183-2196; doi:10.1093/hmg/ddh246
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Human Molecular Genetics, Vol. 13, No. 19 © Oxford University Press 2004; all rights reserved

Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model

Minako Tateno1, Hisako Sadakata1, Mika Tanaka2, Shigeyoshi Itohara2, Ryong-Moon Shin3, Masami Miura3, Masao Masuda3, Toshihiko Aosaki3, Makoto Urushitani1, Hidemi Misawa4 and Ryosuke Takahashi1,*

1Laboratory for Motor System Neurodegeneration and 2Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan, 3Neural Circuits Dynamics Research Group, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan and 4Department of Neurology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan

Received April 21, 2004; Accepted July 20, 2004

Mutant Cu/Zn-superoxide dismutase (SOD1) protein aggregation has been suggested as responsible for amyotrophic lateral sclerosis (ALS), although the operative mediating factors are as yet unestablished. To evaluate the contribution of motoneuronal Ca2+-permeable (GluR2 subunit-lacking) {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors to SOD1-related motoneuronal death, we generated chat-GluR2 transgenic mice with significantly reduced Ca2+-permeability of these receptors in spinal motoneurons. Crossbreeding of the hSOD1G93A transgenic mouse model of ALS with chat-GluR2 mice led to marked delay of disease onset (19.5%), mortality (14.3%) and the pathological hallmarks such as release of cytochrome c from mitochondria, induction of cox2 and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species first accumulated in two fractions dense with neurofilaments/glial fibrillary acidic protein/nuclei and mitochondria long time before disease onset, and then concentrated into the former fraction by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca2+-influx through atypical motoneuronal AMPA receptors thus promotes a misfolding of mutant SOD1 protein and eventual death of these neurons.

* To whom correspondence should be addressed at: Laboratory for Motor System Neurodegeneration, Brain Science Institute, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Tel: +81 484676072; Fax: +81 484624796; Email: ryosuke{at}brain.riken.jp


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