An analysis of apoptotic and autophagic genes in novel Drosophila models of Parkinson disease

M'Angale, Peter Githure (2017) An analysis of apoptotic and autophagic genes in novel Drosophila models of Parkinson disease. Doctoral (PhD) thesis, Memorial University of Newfoundland.

[English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (5MB)

Abstract

Parkinson disease (PD) is the most common neurodegenerative movement disorder in humans and is strongly associated with the selective loss of dopaminergic (DA) neurons. The clinical features include motor dysfunction, resting tremor and in some cases non-motor features such as autonomic, cognitive and psychiatric disorders. The neuropathologic hallmarks are Lewy bodies and Lewy neurites in surviving neurons which are composed of proteinaceous inclusions comprised of α-synuclein, ubiquitin and other proteins. Pathological mechanisms implicated in PD include aberrant protein aggregation, mitochondrial dysfunction, oxidative stress, and failed cellular processes such as apoptosis, autophagy, proteasomal pathway, and several cellular stressors. To analyse the implication and contribution of some of these cellular processes, we altered the expression of the; classical apoptotic genes namely Buffy and Debcl; autophagy genes Atg6 and Pi3K59F; the antiapoptotic transmembrane Bax inhibitor-1 containing motif (TMBIM) family Bax inhibitor-1, Lifeguard and GHITM; mitochondrial genes such as HtrA2, MICU1, porin/VDAC, Pink1 and parkin; and an increased disease risk gene pyridoxal kinase in DA neurons and in the developing eye. We show that the altered expression of key genes can either be detrimental or beneficial to the health of DA neurons as determined by lifespan and locomotor function, in addition to supportive results obtained from biometric analysis of phenotypes from the neuron rich eye. We found that the overexpression of Buffy, the sole pro-survival Bcl-2 homologue in Drosophila could suppress the loss of function-induced phenotypes.

Actions (login required)

View Item