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Title: Investigation of pathogenic mechanisms underlying motor neuron diseases
Author: Fratta, P.
ISNI:       0000 0004 5362 8686
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Motor neuron disease (MND) comprises a group of neurological disorders which include amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), primary muscular atrophy (PMA), spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (SBMA). These disorders have different etiology and clinical features, but share the striking feature of prevalently affecting motor neurons. A genetic cause has been identified for SBMA, SMA and mutations in a handful of genes currently explain a minority of ALS, PLS and PMA cases. Although many different mechanisms have been postulated to play a role in these diseases, the underlying pathogenetic mechanisms are largely unknown and therapeutic interventions are lacking. The research presented in this thesis focuses on two forms of MND (ALS and SBMA) and on the investigation of the causes and mechanisms underlying these diseases. Firstly, the known genetic causes and clinical features were screened and analysed in cohorts of SBMA and ALS patients. Secondly, the role of FUS, a gene known to cause ALS when mutated, as a potential link between ALS and SBMA, was investigated by using a mouse model of SBMA. Finally, the pathogenic mechanisms underlying ALS were analysed, focusing on two important genes: TARDBP and C9orf72. TARDBP mutations cause of <2% of ALS cases, but TDP43, the protein product of TARDBP, is found in the cytoplasmic inclusions of >98% of ALS patients, highlighting its importance in disease pathogenesis. TDP43 is an RNA binding protein and whether RNA defects are present in patient tissue is yet unclear, due to the poor quality of ALS post-mortem material. High quality biopsy material, from a muscle TDP43-disease, sporadic inclusion body myositis, is here used to analyze if RNA changes are associated with TDP43 mislocalization in patient tissue. The results highlight the complex role of TDP43 in this process. Expansions of a hexanucleotide repeat in a non-coding portion of C9orf72 have recently been identified as the underlying cause of 5-20% of ALS cases. The location of the mutation in a non-coding segment, have suggested a potential role for RNA toxicity. The structure of the expanded RNA sequence is therefore here investigated to gain insight in potential pathogenic mechanisms. In summary, a genetic and clinical characterisation of ALS and SBMA cohorts of patients is performed in order to gain insight in the clinical, genetic and molecular mechanisms of these diseases. Further, molecular biology and structural biology tools are used to progress our understanding of the pathogenetic mechanisms linked to two important players in ALS pathogenesis: TDP43 and C9orf72.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available