Abstract
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 (DAOR199W) 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 DAOR199W, promoted the formation of ubiquitinated protein aggregates, activated autophagy and increased apoptosis. The aim of this study was to characterise the effects of DAOR199W in vivo, using transgenic mice overexpressing DAOR199W. Marked abnormal motor features, e.g. kyphosis, were evident in mice expressing DAOR199W, 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< 0.0132). In addition, we crossed the DAOR199W transgenic mouse line with the SOD1G93A mouse model of ALS to determine whether the effects of SOD1G93A were potentiated in the double transgenic line (DAOR199W/SOD1G93A). Although overall survival was not affected, onset of neurological signs was significantly earlier in female double transgenic animals than their female SOD1G93A littermates (125 days vs 131 days, P = 0.0239). In summary, some significant in vivo effects of DAOR199W on motor neuron function (i.e. kyphosis and loss of motor neurons) were detected which were most marked in females and could contribute to the earlier onset of neurological signs in double transgenic females compared to SOD1G93A littermates, highlighting the importance of recognizing gender effects present in animal models of ALS.
Highlights
Amyotrophic lateral Sclerosis (ALS) is the most common adult-onset neuromuscular disorder, caused by the selective degeneration of motor neurons in the spinal cord, brain stem and motor cortex
The most prevalent mutations are found in C9ORF72, SOD1, TAR DNA binding protein 43 (TARDBP), and Fused in Sarcoma (FUS) and much evidence is accumulating to link these mutations with the classical neuropathological features of both familial and sporadic forms of the disease i.e. the accumulation of cytosolic ubiquitinated protein inclusions, most of which are positive for TDP-43 encoded by TARDBP [2]
We have shown that expression of D-amino acid oxidase gene (DAO) containing the mutation associated with familial ALS (FALS), DAOR199W, in primary motor neuron cultures or motor neuron cell lines promotes the formation of ubiquitinated protein aggregates, activates autophagy and increases apoptosis
Summary
Amyotrophic lateral Sclerosis (ALS) is the most common adult-onset neuromuscular disorder, caused by the selective degeneration of motor neurons in the spinal cord, brain stem and motor cortex. The most prevalent mutations are found in C9ORF72, SOD1, TAR DNA binding protein 43 (TARDBP), and Fused in Sarcoma (FUS) and much evidence is accumulating to link these mutations with the classical neuropathological features of both familial and sporadic forms of the disease i.e. the accumulation of cytosolic ubiquitinated protein inclusions, most of which are positive for TDP-43 encoded by TARDBP [2]. It has emerged from these genetic studies that dysfunction of two major pathways are strongly associated with ALS pathogenesis. A less well established area is the understanding of trigger factors that initiate this process which potentially could include glutamate excitotoxicity, impaired calcium homeostasis and oxidative stress
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