Mechanisms of Parkinson's Disease: Lessons from Drosophila

Abstract

The power of Drosophila genetics has attracted attention in tackling important biomedical challenges such as the understanding and prevention of neurodegenerative diseases. Parkinson's disease (PD) is the most common neurodegenerative movement disorder which results from the relentless degeneration of midbrain dopaminergic neurons. Over the past two decades tremendous advances have been made in identifying genes responsible for inherited forms of PD. The ease of genetic manipulation in Drosophila has spurred the development of numerous models of PD, including expression of human genes carrying pathogenic mutations or the targeted mutation of conserved orthologs. The genetic and cellular analysis of these models is beginning to reveal fundamental insights into the pathogenic mechanisms. Numerous pathways and processes are disrupted in these models but some common themes are emerging. These often implicate aberrant synaptic function, protein aggregation, autophagy, oxidative stress, and mitochondrial dysfunction. Moreover, an impressive list of small molecule compounds have been identified as effective in reversing pathogenic phenotypes, paving the way to explore these for therapeutic interventions.

Keywords: Antioxidants; Autophagy; Complex I; DJ-1; Dopamine; Glucocerebrosidase; LRRK2; Mitochondria; Neurodegeneration; Oxidative stress; PINK1; Parkin; Synaptic function; Therapeutic; α-Synuclein.