D-amino acid oxidase controls motoneuron degeneration through D-serine.
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.
Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan. sasabe@a8.keio.jp
Jumpei
J
Sasabe
Yurika
Y
Miyoshi
Masataka
M
Suzuki
Masashi
M
Mita
Ryuichi
R
Konno
Masaaki
M
Matsuoka
Kenji
K
Hamase
Sadakazu
S
Aiso
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000209:etiology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D003605:D-Amino-Acid Oxidase / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006652:Histological Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis; D020125:Mutation, Missense / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D017931:DNA Primers; D012694:Serine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003605:D-Amino-Acid Oxidase