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dc.contributor.authorMurray, Joss
dc.description.abstractSpinal muscular atrophy (SMA) is a motor neuron disease and the primary genetic cause of infant death. This disease is caused by the atrophy of motor neurons in the spinal cord resulting in muscle weakness, gradual paralysis and eventual respiratory defects leading to asphyxiation. SMA is characterised by the depletion of the survival motor neuron (SMN) protein – a ubiquitously expressed protein responsible for the regulation of pre-mRNA splicing. The expression of this protein is vital for the development and survival of all tissues, yet, the question still remains as to why SMN depletion affects predominantly motor neurons. Recent developments in SMA research have introduced a multi-organ SMA phenotype, where other tissues affected share a high energy demand. Furthermore, mitochondrial and glucose metabolism defects have been identified in SMA suggesting an energy deficit, which is particularly detrimental to energy-demanding tissues such as motor neurons. In consideration of this, we established a hypothesis stating that all tissues equally suffer an energy deficit as a result of SMN depletion; however the most energy-demanding tissues are affected to the greatest degree. To address this hypothesis, we employed fibroblasts derived from an SMA type I patient and the carrier parents of this individual to identify metabolic alterations putatively generating an energy deficit. The current study proposes a glycolytic and mitochondrial defect in SMA type I patient fibroblasts that is not present in SMA carrier fibroblasts. Furthermore, we identified elevated levels of the metabolite myoinositol, likely stemming from raised inositol monophosphatase (IMPA1) and inositol-3-phosphate synthase (ISYNA1) - a feature shared in SMN knockdown experiments. Considering the relationship between de novo myoinositol synthesis and glucose metabolism, we propose that SMN depletion promotes myoinositol synthesis at the cost of energy production from glycolysis. Elevated myoinositol has also been identified in a myriad of other neurodegenerative diseases. Therefore, we propose that myoinositol synthesis may hold potential as a therapeutic target for SMA and other related conditions.en_US
dc.rightsAttribution 3.0 United States*
dc.titleTracking the Metabolic Signatures Associated with Spinal Muscular Atrophyen_US
rioxxterms.funderDefault funderen_US
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