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Title: Molecular Mechanisms of DJ-1 Mutations in Parkinson's Disease
Author: Robinson, Alexis Anne
Awarding Body: The School of Pharmacy (University of London)
Current Institution: University College London (University of London)
Date of Award: 2007
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Mutations in PARK7 - the human chromosome Ip36 locus which harbours the DJ-J gene have been shown to be responsible for the onset of autosomal recessive Parkinson's disease. The exact function of DJ-I is unknown due to its diverse role in numerous biological processes including oncogenesis, transcriptional regulation and oxidative stress. This study focuses on the reported missense mutations ofDJ-1 in an attempt to elucidate their pathogenic mechanisms. Effects on DJ-I dimerisation and DJ-I interaction with known protein partners were initially assessed using the yeast two-hybrid system. Results were confinned in a mammalian cell system using af9nity purification methods. This study demonstrated that dlmerisation of DJ-I is required for all DJ-I binding protein interactions, and only mutation Ll66P had an effect on protein dimerisation. DJ-I mutations were found to have a specific disruptive effect on DJ-I interaction with DJ-I binding proteins. Mutation M261 abolished interactions with SUMO-I, a small ubiquitin-like modifier, by an unknown mechanism. Of particular interest was the finding that three distinct DJ-I missense mutations (A104T, Dl49A and E163K) selectively abolished interaction with the so-called DJ-I binding protein (DJBP). Further investigation of DJBP, involving peR amplification from human brain eDNA, revealed the existence of multiple isofonns of DJBP, generated by alternative splicing. Sequence analysis indicated the potential of DJBP to function as a mitochondrially-Iocated calcium-binding protein, due to the identification of EF-hand motifs and an N-tenninal mitochondrial targeting sequence... Disruption of the DJ-I/DJBP interaction may provide a molecular explanation for the underlying cause of DJ-I-related Parkinson's disease. The predicted role of DJBP as a mitochondrially-Iocated calcium-binding protein supports the involvement ofDJ-1 and DJBP in a pathway which exerts a protective effect on the cell under conditions of oxidative stress. Mutations which abolish DJ-I/DJBP interaction may abrogate the protective effect, resulting in increased susceptibility to cellular stress, providing a link between mitochondria and the pathogenesis of Parkinson's disease. These results also suggest that the gene encoding DJBP on human chromosome 22ql3 is a suitable candidate for genetic analysis in Parkinson's disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available