Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS).

Nazanin R. Kondori,Ke Liu,Dominic J. Wells,Praveen Paul,John C. W. Hildyard,Jacqueline P. Robbins,Jacqueline S. de Belleroche

doi:10.3389/fmolb.2018.00008

Abstract

We have investigated a pathogenic mutation in D-amino acid oxidase (DAO), DAOR199W, associated with familial Amyotrophic Lateral Sclerosis (ALS) that impairs D-serine metabolism and causes protein aggregation, autophagy and cell death in motor neuron cell lines. These features are consistent with the pathogenic processes occurring in ALS but most importantly, we have demonstrated that activation of the formation of ubiquitinated protein inclusions, increased autophagosome production and apoptotic cell death caused by the mutation in cell lines are attenuated by 5,7-dichlorokynurenic acid (DCKA), a selective inhibitor of the glycine/D-serine binding site of the NMDA receptor. D-serine is an essential co-agonist at this glutamate receptor. This data provides insight into potential upstream mechanisms that involve the action of D-serine at the NMDA receptor and might contribute to neurodegeneration. This is highly relevant to sporadic ALS (SALS), familial ALS, as well as ALS models, where elevated levels of D-serine have been reported and hence has broader clinical therapeutic implications. In order to investigate this further, we have generated a transgenic line expressing the pathogenic mutation, in order to determine whether mice expressing DAOR199W develop a motor phenotype and whether crossing the SOD1G93A model of ALS with mice expressing DAOR199W affects disease progression. We found that heterozygous expression of DAOR199W led to a significant loss of spinal cord motor neurons at 14 months, which is similar to that found in homozygous mice expressing DAOG181R. We hypothesize that DAO has potential for development as a therapeutic agent in ALS.

Highlights

The focus of this mini-review is to make the case for the potential involvement of D-serine in neurodegenerative diseases which involves impaired activity of D-amino acid oxidase (DAO), the enzyme responsible for its degradation, and is most strongly indicated in Amyotrophic lateral Sclerosis Amyotrophic Lateral Sclerosis (ALS) (ALS)
The typical neuropathological features of ALS are characterized by the accumulation of cytosolic ubiquitinated protein inclusions, most of which are positive for TDP-43, encoded by TAR DNA binding protein 43 (TARDBP) (Neumann et al, 2006)
It has emerged that the majority of pathogenic mutations in FALS occur in genes encoding proteins involved in RNA processing and proteostasis, covering protein folding, the unfolded protein response involved in removal of damaged/mutant proteins, protein trafficking and protein degradation through proteasomal and autophagic pathways, all of which play a fundamental role in normal motor neuron function (Chen and de Belleroche, 2012)

Summary

INTRODUCTION

The focus of this mini-review is to make the case for the potential involvement of D-serine in neurodegenerative diseases which involves impaired activity of D-amino acid oxidase (DAO), the enzyme responsible for its degradation, and is most strongly indicated in Amyotrophic lateral Sclerosis ALS (ALS). We propose that in brain regions such as cerebral cortex, DAO and D-serine in ALS where levels of DAO are very limited, another mechanism may be involved which is mediated through the up-regulation of serine racemase (SR), the biosynthetic enzyme responsible for D-serine biosynthesis.

Background

CONCLUSION

Findings

ETHICS STATEMENT