The role of d-amino acids in amyotrophic lateral sclerosis pathogenesis: a review
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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.
KeywordsAmyotrophic lateral sclerosis (ALS) Motor neuron disease Familial ALS d-Amino acid oxidase (DAO) Serine racemase (SR)
We are grateful to the Motor neurone Disease Association (UK) and American ALS Association for funding this research.
- Almond SL, Fradley RL, Armstrong EJ, Heavens RB, Rutter AR, Newman RJ, Chiu CS, Konno R, Hutson PH, Brandon NJ (2006) Behavioral and biochemical characterization of a mutant mouse strain lacking d-amino acid oxidase activity and its implications for schizophrenia. Mol Cell Neurosci 32:324–334PubMedCrossRefGoogle Scholar
- Chen H-J, de Belleroche J (2012) Endoplasmic reticulum (ER) stress in amyotrophic lateral sclerosis (ALS). In: Agostinis P, Samali A (eds) Endoplasmic reticulum stress in health and disease. Springer, Berlin (in press)Google Scholar
- Matsuo H, Kanai Y, Tokunaga M, Nakata T, Chairoungdua A, Ishimine H, Tsukada S, Ooigawa H, Nawashiro H, Kobayashi Y, Fukuda J, Endou H (2004) High affinity d- and l-serine transporter Asc-1: cloning and dendritic localization in the rat cerebral and cerebellar cortices. Neurosci Lett 358:123–126PubMedCrossRefGoogle Scholar
- Mitchell J, Paul P, Chen HJ, Morris A, Payling M, Falchi M, Habgood J, Panoutsou S, Winkler S, Tisato V, Hajitou A, Smith B, Vance C, Shaw C, Mazarakis ND, de Belleroche J (2010) Familial amyotrophic lateral sclerosis is associated with a mutation in d-amino acid oxidase. Proc Natl Acad Sci USA 107:7556–7561PubMedCrossRefGoogle Scholar
- Wake K, Yamazaki H, Hanzawa S, Konno R, Sakio H, Niwa A, Hori Y (2001) Exaggerated responses to chronic nociceptive stimuli and enhancement of N-methyl-d-aspartate receptor-mediated synaptic transmission in mutant mice lacking d-amino-acid oxidase. Neurosci Lett 297:25–28PubMedCrossRefGoogle Scholar