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Title: Novel properties of hnRNP-UL1 : its possible role in the pathogenesis of ALS
Author: Pratt, Kenny Matthew
ISNI:       0000 0004 5917 219X
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2016
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Heterogeneous nuclear ribonucleoprotein-U like 1 (hnRNP-UL1) is a protein with numerous roles within the cell, including RNA processing and responses to DNA damage. Within this study two novel aspects of the protein are explored: the role of a putative nucleotide-binding domain and the protein's possible involvement in amyotrophic lateral sclerosis (ALS). hnRNP-UL1 is known to have a putative nucleotide-binding domain within its central region containing both a Walker A and Walker B motif. This region had not been investigated previously and was therefore of great interest in this study. The Walker A motif was shown to bind adenosine triphosphate (ATP) and the region appears to possess protein kinase activity. A biological substrate and function for these activities were not established, but these observations suggest that there are still layers of complexity to hnRNP-UL1's cellular roles to be elucidated. ALS is a late-onset neurodegenerative disease with limited treatment strategies and poor patient outcomes. Many of the proteins involved in its pathogenesis have two properties in common: they have roles in RNA-processing and possess prion-like domains (PrLDs). The properties of hnRNP-UL1 appertain to both of these and therefore it was of great interest when ALS patients were discovered with heterozygous hnRNP-UL1 mutations. Results showed that cells possessing the ALS patient mutations (R639C and R468C) had no DNA damage response (DDR) defects or mislocalisation of the protein, but their ssDNA/RNA-binding capability was markedly reduced. Whilst no direct causative links to ALS pathogenesis were shown with the hnRNP-UL1 patient mutations in this study, growing evidence implies good reason for the protein to have involvement in the disease.
Supervisor: Not available Sponsor: Medical Research Council ; University of Birmingham Medical School
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine ; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry