Characterisation of the pathogenic effects of the in vivo expression of an ALS-linked mutation in D-amino acid oxidase: Phenotype and loss of spinal cord motor neurons
Characterisation of the pathogenic effects of the in vivo expression of an ALS-linked mutation in D-amino acid oxidase: Phenotype and loss of spinal cord motor neurons
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DOI：
10.1371/journal.pone.0188912
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发表时间：
2017-12-01
期刊：
影响因子：
3.7
通讯作者：
de Belleroche, Jacqueline S.
中科院分区：
文献类型：
--
作者：
Kondori, Nazanin Rahmani;Paul, Praveen;de Belleroche, Jacqueline S.
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disorder characterised by selective loss of motor neurons leading to fatal paralysis. Current therapeutic approaches are limited in their effectiveness. Substantial advances in understanding ALS disease mechanisms has come from the identification of pathogenic mutations in dominantly inherited familial ALS (FALS). We previously reported a coding mutation in D-amino acid oxidase (DAO(R199W)) associated with FALS. DAO metabolises D-serine, an essential co-agonist at the N-Methyl-D-aspartic acid glutamate receptor subtype (NMDAR). Using primary motor neuron cultures or motor neuron cell lines we demonstrated that expression of DAO(R199W), promoted the formation of ubiquitinated protein aggregates, activated autophagy and increased apoptosis. The aim of this study was to characterise the effects of DAO(R199W) in vivo, using transgenic mice overexpressing DAO(R199W). Marked abnormal motor features, e.g. kyphosis, were evident in mice expressing DAO(R199W), which were associated with a significant loss (19%) of lumbar spinal cord motor neurons, analysed at 14 months. When separated by gender, this effect was greater in females (26%; p
