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Human Molecular Genetics Advance Access published online on August 4, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh246
© 2004 by Oxford University Press
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Article

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

Minako Tateno 1, Hisako Sadakata 1, Mika Tanaka 2, Shigeyoshi Itohara 2, Ryong-Moon Shin 3, Masami Miura 3, Masao Masuda 3, Toshihiko Aosaki 3, Makoto Urushitani 1, Hidemi Misawa 4, Ryosuke Takahashi 5*

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

* To whom correspondence should be addressed. E-mail: ryosuke{at}brain.riken.jp.


  Abstract

Mutant 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 cytochorome 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 (GFAP)/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.


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