D-Amino acid oxidase controls motoneuron degeneration through D-serine

Jumpei Sasabe, Yurika Miyoshi, Masataka Suzuki, Masashi Mita, Ryuichi Konno, Masaaki Matsuoka, Kenji Hamase, Sadakazu Aiso

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving an extensive loss of motoneurons. Aberrant excitability of motoneurons has been implicated in the pathogenesis of selective motoneuronal death in ALS. D-Serine, an endogenous coagonist of N-methyl-D-aspartate receptors, exacerbates motoneuronal death and is increased both in patients with sporadic/familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse). More recently, a unique mutation in the D-amino acid oxidase (DAO) gene, encoding a D-serine degrading enzyme, was reported to be associated with classical familial ALS. However, whether DAO affects the motoneuronal phenotype and D-serine increase in ALS remains uncertain. Here, we show that genetic inactivation of DAO in mice reduces the number and size of lower motoneurons with axonal degeneration, and that suppressed DAO activity in reactive astrocytes in the reticulospinal tract, one of the major inputs to the lower motoneurons, predominantly contributes to the D-serine increase in the mSOD1 mouse. The DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal role in motoneuron degeneration through D-serine regulation and that inactivity of DAO is a common feature between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of reducing D-serine or controlling DAO activity in ALS should be tested in future studies.

Original languageEnglish
Pages (from-to)627-632
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number2
DOIs
Publication statusPublished - 2012 Jan 10

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D-Amino-Acid Oxidase
Motor Neurons
Serine
Amyotrophic Lateral Sclerosis
Mitogen-Activated Protein Kinase Kinases
Glutamate Receptors
N-Methyl-D-Aspartate Receptors
Astrocytes
Neurodegenerative Diseases
Down-Regulation
Phenotype

Keywords

  • 2D-HPLC
  • Enzyme histochemistry
  • Excitotoxicity
  • Motor neuron disease
  • Neurodegeneration

ASJC Scopus subject areas

  • General

Cite this

D-Amino acid oxidase controls motoneuron degeneration through D-serine. / Sasabe, Jumpei; Miyoshi, Yurika; Suzuki, Masataka; Mita, Masashi; Konno, Ryuichi; Matsuoka, Masaaki; Hamase, Kenji; Aiso, Sadakazu.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 2, 10.01.2012, p. 627-632.

Research output: Contribution to journalArticle

Sasabe, Jumpei ; Miyoshi, Yurika ; Suzuki, Masataka ; Mita, Masashi ; Konno, Ryuichi ; Matsuoka, Masaaki ; Hamase, Kenji ; Aiso, Sadakazu. / D-Amino acid oxidase controls motoneuron degeneration through D-serine. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 2. pp. 627-632.
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