Modelling Motor Neuron Disease using Induced Pluripotent Stem Cells

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease. The majority of ALS cases are sporadic (SALS), but 10% of patients have a familial form of ALS (FALS). Mutations in Fused in Sarcoma (FUS) occur in approximately 4% of FALS and less than 1% of SALS. A hallmark feature of ALS is the degeneration of upper and lower motor neurons in the brain and spinal cord; however, the mechanism underlying this loss is not known. Studies of degenerative mechanisms have been impeded by the inaccessibility of human neural tissue. A possible solution is to use induced pluripotent stem cells (iPSCs) derived from patients, which may be differentiated into the cell types affected by disease.

To test whether patient-specific stem cells can be used to model aspects of ALS pathogenesis, iPSC lines were generated from a patient carrying the pathogenic FUS R521C mutation. FUS iPSCs derived from patient fibroblasts and WT iPSCs derived from fibroblasts from two healthy controls were differentiated into neural progenitors and motor neurons. FUS iPSC-derived neuronal cells recapitulate key aspects of FUSassociated ALS, including mislocalisation of FUS protein, the redistribution of FUS protein into cytoplasmic stress granules, and increased apoptotic cell death.

The second study uses this iPSC model to investigate the effects of mutant FUS on dendritic morphology and synaptic regulation. FUS iPSC-derived neurons display abnormal dendritic morphology, such as reduced neurite outgrowth and reduced density of dendritic protrusions. FUS iPSC-derived neurons also show differences in the localisation of synaptic proteins. This study suggests that physiological levels of mutant FUS protein affect the morphology and synaptic structure of human neurons.

These studies validate the stem cell approach to disease modelling and provide support for the use of patient-specific stem cells for the study of disease mechanisms.
Date of Award2016
Original languageEnglish
Awarding Institution
  • King's College London

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