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Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS

Citation

Rembach, A and Turner, BJ and Bruce, S and Cheah, IK and Scott, RL and Lopes, EC and Zagami, CJ and Beart, PM and Cheung, NS and Langford, SJ and Cheema, SS, Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS, Journal of Neuroscience Research, 77, (4) pp. 573-582. ISSN 0360-4012 (2004) [Refereed Article]

DOI: doi:10.1002/jnr.20191

Abstract

Glutamate excitotoxicity is strongly implicated as a major contributing factor in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Excitotoxicity results from elevated intracellular calcium ion (Ca2+) levels, which in turn recruit cell death signaling pathways. Recent evidence suggests that -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit (GluR) stoichiometry is a dominant factor leading to excess Ca2+ loading in neurodegeneration. In particular, the Ca2+ permeable glutamate receptor subunit 3 (GluR3) has been implicated in several neurologic conditions such as bipolar disorder and epilepsy. Recent proteomic analysis within our group on the copper zinc superoxide dismutase (SOD1) G93A transgenic mouse model of familial ALS (FALS) reveals a potentially deleterious upregulation of GluR3 in spinal cord compared to that in wild-type littermates. Based on this finding we designed a 12mer antisense peptide nucleic acid (PNA) directed against GluR3. This sequence significantly reduced levels of GluR3 protein and protected neuroblastoma x spinal cord (NSC-34) cells against death induced by the AMPA receptor-specific agonist (S)-5-fluorowillardiine. We subsequently treated SOD1G93A mice thrice weekly with intraperitoneal injections of the antisense PNA (2.5 mg/kg) commencing at postnatal day 50. Mice treated with the antisense sequence had significantly extended survival compared to mice injected with a nonsense sequence. Western blot analysis, however, did not reveal a significant reduction in GluR3 protein levels in whole extracts of the lumbar spinal cord. These results suggest that interference with the GluR3 component of the AMPA receptor assembly may be a novel strategy for controlling excitotoxic destruction of motor neurons and may lead to new therapeutic opportunities for the treatment of human ALS.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Cellular Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Cheung, NS (Dr Nam Cheung)
ID Code:61568
Year Published:2004
Web of Science® Times Cited:40
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-03-04
Last Modified:2010-05-03
Downloads:0

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