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Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

Authors Le Verche V, Ikiz B, Jacquier A, Przedborski S, Re D

Published 22 December 2010 Volume 2011:4 Pages 1—22


Review by Single anonymous peer review

Peer reviewer comments 3

Virginia Le Verche1,3, Burcin Ikiz4, Arnaud Jacquier1,3, Serge Przedborski1–3, Diane B Re1,3
1Departments of Neurology, 2Pathology and Cell Biology, and the 3Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, USA; 4Ms Burcin Ikiz is a graduate student in the program of Neurobiology and Behavior at Columbia University

Abstract: The cause of the fatal motor neuron disease, amyotrophic lateral sclerosis (ALS), remains largely unknown. Most cases of ALS are sporadic and, for ~20% of familial ALS patients, mutations in the superoxide dismutase-1 (SOD1) gene have been identified. Transgenic rodents overexpressing mutant SOD1 emulate the disease and constitute the best ALS animal model so far. Several lines of evidence suggest that ALS is a multifactorial condition. In this review, we discuss the question of the involvement of the glutamate pathways in ALS-induced motor neuron death. As such, we review the data implicating glutamate metabolism alterations, glutamatergic environmental toxins, glutamate transporter/receptor defects, and Ca2+-mediated glutamate toxicity in the etiopathogenesis of ALS. Given the published data, we contend that glutamate-induced neurotoxicity more likely precipitates motor neuron degeneration rather than being the initiating factor of ALS. Furthermore, we propose that glutamate-induced neurotoxicity participates in the ALS deadly molecular cascade only as an executioner to put an end to a series of molecular perturbations that have irreversibly compromised motor neuron function. This could provide an explanation for the modest effect of therapeutic strategies targeting the glutamatergic system, including the only currently FDA-approved ALS treatment, riluzole. As in diseased motor neurons, overwhelming Ca2+ overload may be the converging point for glutamate, endoplasmic reticulum stress, and mitochondrial dysfunctional pathways, and only therapies targeting these simultaneously or targeting the earliest alterations initiating this deleterious cascade may have a real impact on halting ALS progression.

Keywords: glutamate, excitotoxicity, amyotrophic lateral sclerosis, glutamate receptors, glutamate transporters, calcium


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