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Title: The molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro models
Author: Kent, Louisa
ISNI:       0000 0004 6346 403X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by degeneration of both upper and lower motor neurons. Most ALS occurs in a sporadic manner, though 5-10% is familial. Fused in sarcoma (FUS) is an RNA binding protein, and mutations in the FUS gene are responsible for approximately 4% of familial and < 1% of sporadic ALS cases. This work uses in vitro and in vivo models to examine the cellular effects of FUS mutations and the potential mechanisms of motor neuron toxicity. The first section describes a family with a severe clinical form of ALS due to a FUS truncation mutation p.G504Wfs*12. This mutation demonstrates a severe phenotype in vitro, with mislocalisation of mutant FUS from the nucleus to the cytoplasm, and co-localisation with stress granules. Comparing these results with other mutations highlights the correlation between FUS mislocalisation and clinical phenotype, suggesting that the distribution of FUS plays a role in the pathogenesis of ALS. The next section explores the phenotype of primary motor neurons from a FUS BAC transgenic mouse model expressing low levels of wild-type or P525L human FUS. P525L-FUS shows marked mislocalisation to the cytoplasm and co-localisation with stress granules, with evidence of reduced survival and alterations in stress granule dynamics. This suggests that motor neurons expressing mutant FUS show inherent vulnerability. The final section explores transcript levels and alternative splicing in both FUS and TDP-43 BAC transgenic mouse models. Key proteins such as TDP-43, FUS and SMN show alterations in mRNA levels in CNS tissue, and some subtle splicing alterations are described. This work suggests that mutations in FUS are likely to affect motor neurons even when expressed at very low levels. Alterations in FUS distribution, stress granule dynamics, and regulation of transcription may all play a part in conferring a susceptibility to developing ALS.
Supervisor: Talbot, Kevin Sponsor: Patrick Berthoud Charitable Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available