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Title: Cellular phenotypes associated with autism : an iPSC study
Author: Kathuria, Annie
ISNI:       0000 0004 5921 2876
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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Autism is a neurodevelopmental disorder that affects around 700,000 in the UK (Baird G. et al., 2006; Burgha et al., 2011) and these numbers are constantly increasing. Nonetheless, our understanding of the cellular and molecular processes underlying autism is limited. This has hindered the development of effective treatments and created a need for human specific models. The potential of modeling autism through the use of human induced pluripotent stem cells (iPSCs) is an exciting advancement towards uncovering the mechanisms underlying a disorder that affects the lives of so many people. Recent studies report that mutations in the SHANK3 gene are a major cause of autism (Nemirovsky et al., 2015; Bentancur et al., 2013; Buccoto, 2013). This project aimed to track and compare the development of neurons generated from iPSCs lines derived from SHANK3 patients and healthy individuals. These lines were produced from hair root biopsies from three categories of individuals: three healthy control individuals, two autistic patients with a heterozygous deletion in the SHANK3 gene and one sporadic ASD individual. iPSCs were differentiated into hypothalamic neurons and their structural and functional development was tracked during the various stages of neuralisation. These studies revealed that during early neuronal development, SHANK3 iPSC derived neurons have a smaller cell soma, but more and longer primary neurites than control cells. These morphogenetic deficits were rescued by overexpressing SHANK3. Further, embryonic stem cell lines, with homozygous and heterozygous deletion of the SHANK3 gene, gave rise to neurons with similar morphogenetic deficits to those seen in the SHANK3 patient neurons. Both studies validate that the reduced expression of SHANK3 is the cause for these morphogenetic deficits. The discovery of these early morphological defects in human SHANK3 mutant neurons has provided new insight into the mechanisms underpinning autism. This research has also developed a robust cell-based platform that can, not only be used to test these potential mechanisms, but also as a screen for potential therapies.
Supervisor: Srivastava, Deepak Prakash ; Price, Jack Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available