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Title: Molecular and genetic characterisation of Drosophila PINK1
Author: Ho, Venus Ming-Wai
ISNI:       0000 0004 2724 8209
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2010
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Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder, which is characterised by the degeneration of dopaminergic neurons. The molecular mechanisms that lead to PD are unknown. A number of genes have been identified to be associated with inherited forms of PD, including PINK1 and Parkin, which are linked to autosomal recessive juvenile parkinsonism. It has been demonstrated in the Drosophila melanogaster model system that PINKl and Parkin function in a common pathway. The work of this thesis aims to characterise PINKI molecularly and genetically in Drosophila . One approach that was taken is to conduct an unbiased genetic screen to identify novel genes that interact with PINKl. This screen uses a rough-eye phenotype that is caused by overexpression of PINKl in the eye tissue. Deficiency chromosomes that result in modification to the rough-eye phenotype indicate the deficiency region spans a gene or genes that may be involved in the normal function of PINKl. Another approach is to identify candidate genes that may have a role with PINK1 function. Drosophila PINK1 and Parkin mutants exhibit a distinct set of mutant phenotypes. Similar phenotypes are also seen with Rhomboid-7 mutants, which suggest Rhomboid-7 to be a potential candidate gene. This was tested genetically and biochemically. An alternative approach to understand the way PINK1 functions is based on the fact that there are two forms of PINKl. The functional importance of having two forms of PINK1 and the site of their function is unknown. A putative PINK1 form was designed to mimic the PINKl processed form located to the cytoplasm. This was analysed functionally against PINK1 and Rhomboid-7. The result shows that Rhomboid-7, a mitochondrial intramembrane protease, is required for the processing of PINKl, resulting in two detectable forms. The significance of having two forms ofPINKl is unclear. The processed PINK! in the cytoplasm can rescue PINK! mutant phenotypes but not that of Rhomboid-7. This suggests that processed PINKl has no role in the functionality of Rhomboid-7. In conclusion, Rhomboid-7 was identified as a novel component of the PINK! pathway, which acts to cleave full length PINKl. The putative processed PINK1 form was able to rescue PINK 1 function.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available