Degradation and degeneration :synergistic impact of autophagy and mitochondrial dysfunction in Parkinson's disease

Abstract

The single greatest risk factor for the development of idiopathic Parkinson’s Disease is advancing age. The differences at the cellular level that cause some individuals to develop this highly debilitating disease over healthy ageing are not fully understood. Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD) since the drug MPTP, known to cause Parkinson’s like symptoms, was shown to invoke its deleterious effect through inhibition of Complex I (CI) of the mitochondrial electron transport chain. Since this discovery in the 1980s, several causative genes in the much rarer familial forms of PD have been shown to encode proteins which function within, or in association with mitochondria. Through inherited cases of the disorder the process through which mitochondria are removed, mitophagy, a specialized form of autophagy has also been associated with the pathogenesis that leads to en masse cell death in this disorder. This work explores the interplay between mitochondrial deficiencies, through complex I dysfunction, and changes to autophagic processes. The methodologies to enable these observations are also described in detail with the development of novel and specialized techniques necessary to answer many of the specific research questions. The mechanisms behind complex I deficiency’s impact upon cellular processes is also explored as part of this thesis. Mitochondria and autophagy are irrevocably linked through mitochondrial dynamics, to this end an exploration of the greater impact complex I dysfunction has upon mitochondrial motility, fission and fusion was investigated. As the most prevalent neurodegenerative movement disorder of old age, understanding the molecular changes that result in Parkinson's Disease is vital to increase knowledge and offer novel therapeutic targets. Parallel studies in human upper midbrain tissue and cybrid cell lines within this work have revealed significant changes to both autophagy and mitochondrial dynamics in response to complex I deficiency. Given that mitochondrial ‘health’ and autophagic regulation directly impact upon one another identifying how exactly these may contribute to neuronal loss will hopefully allow therapeutic modulation at a point of PD pathogenesis where cells can still be retained.