New insights into the role of pten-induced kinase 1 (pink1) in parkinson disease using a drosophila model

Todd, Amy M. (2012) New insights into the role of pten-induced kinase 1 (pink1) in parkinson disease using a drosophila model. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Parkinson disease (PD) is the most prevalent human neurodegenerative movement disorder. Hereditary and sporadic forms of PD share pathological features including oxidative stress, protein aggregation and mitochondrial dysfunction. PINK1 (PTEN induced putative kinase 1) encodes a serine-threonine kinase linked to autosomal recessive and sporadic PD. With no animal models available at the commencement of this thesis, it was our goal to study the gene within a Drosophila model of the disease. We identified a Drosophila melanogaster homologue of PINK1 , and used transgenics to employ expression studies along with morphological, longevity and behavioural assays. We have found that Pink1 is able to improve the effects of toxic proteins, including overcoming the effects of α-synuclein and Gal4 overexpression. Our results suggest that increases in α-synuclein and Pink1 together can have a synergistic effect, allowing for enhanced protection and increased functional longevity. Additionally, our studies have identified the possibility of a non-protective role for the Pink1/parkin pathway. We have found that an increase in Pink1 or parkin is able to increase the damaging effects of the directed over-expression of Foxo in Drosophila, highlighting a possible role in the apoptotic pathway. Taken together, our research highlights the complex role of Pink1, where it likely functions in a Pink1/parkin pathway to operate in the ubiquitin-proteasomal system, regulate mitochondrial fission/fusion events, regulate membrane permeability during apoptosis, and other roles that may be independent of its kinase function. Further investigation into the Pink1 mechanism of action will be important for the future development of disease modifying therapies for Parkinson disease.

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