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

Minako Tateno, Hisako Sadakata, Mika Tanaka, Shigeyoshi Itohara, Ryong Moon Shin, Masami Miura, Masao Masuda, Toshihiko Aosaki, Makoto Urushitani, Hidemi Misawa, Ryosuke Takahashi

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116 Citations (Scopus)

Abstract

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) α-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.

Original languageEnglish
Pages (from-to)2183-2196
Number of pages14
JournalHuman molecular genetics
Volume13
Issue number19
DOIs
Publication statusPublished - 2004 Oct 1
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Tateno, M., Sadakata, H., Tanaka, M., Itohara, S., Shin, R. M., Miura, M., Masuda, M., Aosaki, T., Urushitani, M., Misawa, H., & Takahashi, R. (2004). Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model. Human molecular genetics, 13(19), 2183-2196. https://doi.org/10.1093/hmg/ddh246