The role of D-amino acids in amyotrophic lateral sclerosis pathogenesis: a review

Abstract

A potential role for D-amino acids in motor neuron disease/amyotrophic lateral sclerosis (ALS) is emerging. D-Serine, which is an activator/co-agonist at the N-methyl-D-aspartate glutamate receptor subtype, is elevated both in spinal cord from sporadic cases of ALS and in an animal model of ALS. Furthermore, we have shown that a mutation in D-amino acid oxidase (DAO), an enzyme strongly localized to spinal cord motor neurons and brain stem motor nuclei, is associated with familial ALS. DAO plays an important role in regulating levels of D-serine, and its function is impaired by the presence of this mutation and this may contribute to the pathogenic process in ALS. In sporadic ALS cases, elevated D-serine may arise from induction of serine racemase, its synthetic enzyme, caused by cell stress and inflammatory processes thought to contribute to disease progression. Both these abnormalities in D-serine metabolism lead to an increase in synaptic D-serine which may contribute to disease pathogenesis.