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Investigating the pathophysiology of Amyotrophic Lateral Sclerosis using human induced pluripotent stem cell technology
|Miles, Gareth Brian
|Amyotrophic Lateral Sclerosis (ALS) is a devastating, adult onset, neurodegenerative disease which remains largely untreatable and incurable, reflecting an incomplete understanding of the key pathogenic mechanisms that underlie motoneuron (MN) loss in the disease. Through the use of induced pluripotent stem cell (iPSCs) technology, cells from the human central nervous system can be studied at a range of time points, including those prior to overt pathology, in order to understand early causative events in ALS. In the present study, human iPSC-derived MNs and astrocytes were used to study the pathophysiology of ALS. Whole-cell patch clamp recording techniques were utilised to investigate whether the functional properties of human iPSC-derived MNs are altered in cells derived from ALS patients compared to those from healthy controls. Patient iPSC-derived MNs harbouring C9ORF72 or TARDBP mutations display an initial period of hyperexcitability followed by a progressive loss of action potential output due to decreases in voltage-activated Na+ and K+ currents. These changes occur in the absence of changes in cell viability. Given evidence in support of non-cell autonomous disease mechanisms in ALS, the potential involvement of interactions between neurons and astrocytes in the pathophysiological phenotype were next investigated. Patient iPSC-derived astrocytes harbouring C9ORF72 or TARDBP G298S mutations cause a loss of functional output in control iPSC-derived MNs, due to a progressive decrease in voltage-activated Na+ and K+ currents. These data show that patient iPSC-derived astrocytes can induce pathophysiological changes in control human iPSC-derived MNs which are similar to those revealed in patient iPSC-derived MNs. This study also utilizes pharmacological agents and genetic editing to demonstrate that the pathophysiological phenotype can be altered. Overall, this study implicates MN dysfunction, potentially due to non-cell autonomous disease mechanisms, as an early contributor to downstream degenerative pathways that ultimately lead to MN loss in ALS.
|University of St Andrews
|Investigating the pathophysiology of Amyotrophic Lateral Sclerosis using human induced pluripotent stem cell technology
|Euan MacDonald Centre for Motor Neurone Disease Research
|Motor Neurone Disease Association (Great Britain)
|PhD Doctor of Philosophy
|The University of St Andrews
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