Experimental approaches for elucidating co-agonist regulation of NMDA receptor in motor neurons: Therapeutic implications for amyotrophic lateral sclerosis (ALS)

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Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterised by selective loss of motor neurons leading to fatal paralysis. Although most cases are sporadic, approximately 10% of cases are familial and the identification of mutations in these kindred has greatly accelerated our understanding of disease mechanisms. To date, the causal genes in over 70% of these families have been identified. Recently, we reported a mutation (R199W) in the enzyme that degrades d-serine, d-amino acid oxidase (DAO) and co-segregates with disease in familial ALS. Moreover, d-serine and DAO are abundant in human spinal cord and severely depleted in ALS. Using cell culture models, we have defined the effects of R199W-DAO, and shown that it activates autophagy, leads to the formation of ubiquitinated protein aggregates and promotes apoptosis, all of which processes are attenuated by a d-serine/glycine site antagonist of the N-methyl d-aspartate receptor (NMDAR). These findings suggest that the toxic effects of R199W-DAO are at least in part mediated via the NMDAR involving the d-serine/glycine site and that an excitotoxic mechanism may contribute to disease pathogenesis.

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