AMPA receptor-mediated neuronal death in sporadic ALS
Version of Record online: 19 JAN 2010
© 2010 Japanese Society of Neuropathology
Volume 30, Issue 2, pages 182–188, April 2010
How to Cite
Kwak, S., Hideyama, T., Yamashita, T. and Aizawa, H. (2010), AMPA receptor-mediated neuronal death in sporadic ALS. Neuropathology, 30: 182–188. doi: 10.1111/j.1440-1789.2009.01090.x
- Issue online: 21 MAR 2010
- Version of Record online: 19 JAN 2010
- Received 30 October 2009 and accepted 10 November 2009.
- AMPA receptor;
- RNA editing
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-mediated excitotoxicity has been proposed to play a role in death of motor neurons in amyotrophic lateral sclerosis (ALS). We demonstrated that RNA editing of GluR2 mRNA at the glutamine/arginine (Q/R) site was decreased in autopsy-obtained spinal motor neurons, but not in cerebellar Purkinje cells, of patients with sporadic ALS. This molecular change occurs in motor neurons of sporadic ALS cases with various phenotypes, but not in degenerating neurons of patients with other neurodegenerative diseases, including SOD1-associated familial ALS. Because GluR2 Q/R site-editing is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2), it is likely that regulatory mechanism of ADAR2 activity does not work well in the motor neurons of sporadic ALS. Indeed, ADAR2 expression level was significantly decreased in the spinal ventral gray matter of sporadic ALS as compared to normal control subjects. It is likely that ADAR2 underactivity selective in motor neurons induced deficient GluR2 Q/R site-editing, which results in the neuronal death of sporadic ALS. Thus, among multiple different molecular mechanisms underlying death of motor neurons, it is likely that an increase of the proportion of Q/R site-unedited GluR2-containing Ca2+-permeable AMPA receptors initiates the death of motor neurons in sporadic ALS. To this end, normalization of ADAR2 activity in motor neurons may become a therapeutic strategy for sporadic ALS.