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Title: In vitro and pathological investigation of dipeptide repeat proteins in C9orf72 linked frontotemporal dementia and amyotrophic lateral sclerosis
Author: Gittings, Lauren Marie
ISNI:       0000 0004 7660 0643
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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An intronic hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of two clinically, genetically and pathologically overlapping neurodegenerative disorders, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The pathogenic mechanism of disease is currently unknown, but it is hypothesised that toxicity may, at least in part, be attributed to dipeptide repeat (DPR) proteins that are produced as a result of unconventional repeat associated non-ATG initiated (RAN) translation of the hexanucleotide repeat. In this thesis, cellular models and post-mortem tissue from C9orf72 mutation patients have been used to further characterise various properties of the DPR proteins that have been previously shown to be the most toxic; poly-glycine-alanine (poly-GA), poly-proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR). Overexpression of DPR proteins in SK-N-SH cells was used to assess the ability of a molecular chaperone to reduce the aggregation of these proteins, and CRISPR-Cas9 technology was used to fluorescently tag endogenous DPR proteins in C9orf72 patient induced pluripotent stem cells. In addition to cellular models, post-mortem brain tissue from C9orf72 patients was used to identify the presence and characterise the pathological significance of methylated forms of the arginine-containing DPR proteins, poly-PR and poly-GR. Additionally, this thesis contains research on another pathological subtype of FTD; FTLD-FUS. Immunohistochemistry was used to identify and characterise two abundant RNA binding proteins, hnRNP R and Q, which were found to accumulate in pathological inclusions specifically in FTLD-FUS patient post-mortem tissue.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available