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Title: Parkinson's disease-associated proteins : studying their role in mitophagy with cellular and Drosophila models
Author: Martinez Zarate, A.
ISNI:       0000 0004 6425 2944
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Parkinson's Disease (PD) is the second most common neurodegenerative disease, for which there is no effective treatment or biomarker. In about 10% of the cases PD is caused by mutations in PD-associated genes. Amongst these genes, the E3 ubiquitin-ligase Parkin and the Ser/Thr kinase PINK1 have been reported to act in a common pathway as key regulators of mitophagy, a selective type of autophagy where mitochondria are engulfed and degraded in the lysosomes. However, the molecular mechanisms leading to PD and the involvement of distinct PD-associated genes in mitophagy is unclear. Here, I studied basal and Parkin-dependent mitophagy in several cellular and Drosophila models, and employed these systems to check the involvement of selected PD-associated proteins in mitophagy. I report that USP30 regulates both, basal and Parkin-dependent mitophagy, showing that USP30 is a druggable target to modulate mitophagy. In addition, I studied the role of Parkin in Drosophila neurons and showed that Parkin activity affects locomotion and survival. Moreover, I have sought in vivo Parkin substrates by performing a mass spectrometry proteomic study employing a fly model that constitutively expresses biotinylated ubiquitin. This led to the identification of both established and novel Parkin substrates, amongst which I found the PDassociated protein VPS35. Finally, I generated a mitophagy reporter fly by introducing mt-Keima and briefly studied mitophagy in vivo. All together, the work performed during this thesis will set the basis for further studies to identify physiologically relevant Parkin substrates and to analyse mitophagy in vivo employing the mt-Keima flies.
Supervisor: Clague, M. ; Mayor, U. ; Urbe, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral