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Title: Clinicogenetic and functional studies in rare hereditary neurodegenerative movement disorders
Author: Wiethoff, S.
ISNI:       0000 0004 7230 8223
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Neurodegenerative diseases are equally fascinating as they are devastating. They illustrate both function and pathology of neurons, the most complex cells in the human body. In the past, technological progress has allowed the identification of genetic variation that can lead to neurodegenerative processes. However, for many patients with different neurodegenerative diseases to date, no genetic diagnosis is obtained despite thorough investigation. For another significant proportion of neurodegenerative diseases the genetic defect and the resulting clinical phenotype/spectrum is known, but exact pathomechanisms remain elusive. This delays successful translational research and eventual clinical treatment. The objective of this thesis is to combine both aspects and employ two main techniques to further advance the search for better pathophysiologic understanding of neurodegenerative diseases: whole exome sequencing (WES) and induced pluripotent stem cell (iPSC) technology. Firstly, the thesis aims to improve clinical characterisation and genetic analysis of neurodegenerative patients to identify genetic causes and genetic modifiers of disease. Secondly, it aims to establish functional models in search of pathogenic and potentially druggable mechanisms using iPSCs in clinically and genetically characterised groups of patients. This thesis thereby investigated the clinicogenetic and pathophysiological bases of rare hereditary movement disorders with focus on hereditary ataxias, trinucleotide repeat and complex parkinsonism disorders, including neurodegeneration with brain iron accumulation (NBIA). Clinical characterisation, WES, targeted sequencing, homozygosity mapping and traditional Sanger sequencing were used to yield clinical description, identify underlying genetic causes and to investigate disease modifiers in different trinucleotide repeat disorders. To finally establish functional readouts of pathogenic mutations in a well characterised patient cohort, iPSC technology and directed differentiation was used to create a human neuronal model of spinocerebellar ataxia type 15 and to derive non-forebrain neuronal precursors to facilitate the study of cerebellar diseases using iPSCs in the future.
Supervisor: Houlden, H. H. ; Hardy, J. H. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available