Novel properties of hnRNP-UL1: its possible role in the pathogenesis of ALS

Pratt, Kenny Matthew (2016). Novel properties of hnRNP-UL1: its possible role in the pathogenesis of ALS. University of Birmingham. Ph.D.

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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.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cancer and Genomic Sciences
Funders: Medical Research Council, Other
Other Funders: The University of Birmingham
Subjects: R Medicine > RC Internal medicine
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry


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