Modeling neurodegeneration using
induced pluripotent stem cells (iPSCs)
Lauren Watson
Division of Human Genetics
Institute of Infectious Disease and Molecular Medicine
Faculty of Health Sciences
University of Cape Town
Networking the Brain · UCT Cortex Club Inaugural Symposium · November 2014
Modeling neurodegeneration using
induced pluripotent stem cells (iPSCs)
• Research focus: Molecular basis of inherited conditions
• Spinocerebellar Ataxia type 7 = Late-onset
neurodegenerative disease
• Major clinical manifestations: gait ataxia, macular atrophy
• Caused by polyQ expansion in Ataxin-7 → toxic gain of
function
• Pathological hallmark = protein aggregates
• Ataxin-7 forms part of TFTC/STAGA transcription
coactivator complexes
• Transcriptional dysregulation = early marker of disease
• Problem: Lack of disease-relevant cell models
2 | Lauren Watson| Division of Human Genetics| Modeling neurodegeneration using iPSCs| 7 November 2014
Generation of iPSC-based neuronal models
Robinton and Daley 2012
3 | Lauren Watson| Division of Human Genetics| Modeling neurodegeneration using iPSCs| 7 November 2014
Significance and impact
• Greater understanding of pathogenesis of
neurodegeneration, particularly regarding transcriptional
dysregulation and cell stress response
• Generation of cellular model of in vitro aging
• Identification of disease phenotype which can be used to
screen potential therapies
• Use as a “pre- pre-clinical” screening tool, particularly in
SA
4 | Lauren Watson| Division of Human Genetics| Modeling neurodegeneration using iPSCs| 7 November 2014
Techniques and Expertise
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Anything to do with DNA!
Sequencing and genotyping
Immunocytochemistry
qPCR
Cell culture
iPSC reprogramming
iPSC characterisation
Neuronal differentiation
CRISPR/Cas9-mediated gene editing
5 | Lauren Watson| Division of Human Genetics| Modeling neurodegeneration using iPSCs| 7 November 2014
Why Neuroscience?
• “By accident”
• Functional analysis of gene mutations
• Study inherited neurodegenerative disease in
tissue of interest
6 | Lauren Watson| Division of Human Genetics| Modeling neurodegeneration using iPSCs| 7 November 2014
Career path
• BSc  PhD at UCT
• Commonwealth Split-site Scholarship (Oxford)
• Future: Postdoctoral fellowship at University of
Oxford (2015)
• Apply for everything!
• Collaborate, network (conferences),
learn (research visits), find a mentor
• Work with a legacy in mind
7 | Lauren Watson| Division of Human Genetics| Modeling neurodegeneration using iPSCs| 7 November 2014
The future of Neuroscience at UCT
• Main focus of our group: disease modeling using
iPSCs
• UCT Stem Cell Research Initiative
• Scope to expand to other inherited conditions
using our platform
• We provide the cells, you
provide the neuroscience
applications!
stemcells.uct.ac.za
8 | Lauren Watson| Division of Human Genetics| Modeling neurodegeneration using iPSCs| 7 November 2014
Acknowledgements
University of Oxford
Prof Matthew Wood
Dr Sally Cowley
Ms Jane Vowles
Dr Helen Curtis
Dr Miguel Varela
Dr Liz Hartfield
Wood Lab
James Martin Stem Cell Unit
University of Cape Town
Prof Jacquie Greenberg
Prof Sue Kidson
Dr Robea Ballo
Dr Danielle Smith
Dr Joseph Raimondo
Mr Richard Burman
Ms Fiona Baine
Hum Gen Lab
UCT Stem Cell Research Initiative
The Scripps Research Institute (USA)
Assoc Prof Marco Weinberg
Morris Lab
Dr Mahito Nakanishi (National Institute of Advanced
Industrial Science and Technology, Japan)
Dr Janine Scholefield (CSIR)
Funding
Harry Crossley Foundation, NRF, MRC, Commonwealth
Scholarships Commission, Ataxia UK, John Fell OUP Fund,
UCT, National Ataxia Foundation, Keystone Symposia
9 | Lauren Watson| Division of Human Genetics| Modeling neurodegeneration using iPSCs| 7 November 2014