Abstract

Mitochondria are a nexus of life and death of the cell and have long been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD). Genetic analysis of inherited PD has identified single-gene mutations responsible for rare forms of PD. Understanding the consequence of these mutations can potentially illuminate the pathogenic mechanisms underlying all forms of PD. These mutations can be modelled in genetically tractable model systems, such as the fruit fly, Drosophila melanogaster, which has proven a remarkably informative model. Loss of function in parkin and PINK1 cause the majority of early onset PD. It was established using Drosophila that PINK1 and parkin act in a common pathway to maintain mitochondrial homeostasis. Mitochondria localised PINK1 is required to signal parkin translocation to dysfunctional mitochondria where ubiquitination of multiple outer membrane targets, such as Mitofusins, promotes their isolation and degradation by autophagy (mitophagy). In neurons, these mitochondria must also be transported large distances for degradation. The inability to properly regulate mitochondrial turnover will impact on the long-term maintenance of the mitochondrial network and ultimately on neuronal survival, suggesting a possible pathogenic mechanism for PD, however, the physiological in vivo evidence is limited. In addition, many details of the molecular mechanism and other pathway components are unclear. Our work aims to addresses these deficiencies using Drosophila as a model system.