Mechanisms of Parkinson's Disease: Lessons from Drosophila.

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.

Effects of five Ayurvedic herbs on locomotor behaviour in a Drosophila melanogaster Parkinson's disease model.

Current conventional treatments for Parkinson's disease (PD) are aimed at symptom management, as there is currently no known cure or treatment that can slow down its progression. Ayurveda, the ancient medical system of India, uses a combination of herbs to combat the disease. Herbs commonly used for this purpose are Zandopa (containing Mucuna pruriens), Withania somnifera, Centella asiatica, Sida cordifolia and Bacopa monnieri. In this study, these herbs were tested for their potential ability to improve climbing ability of a fruit fly (Drosophila melanogaster) PD model based on loss of function of phosphatase and tensin-induced putative kinase 1 (PINK1). Fruit flies were cultured on food containing individual herbs or herbal formulations, a combination of all five herbs, levodopa (positive control) or no treatment (negative control). Tests were performed in both PINK1 mutant flies and healthy wild-type (WT) flies. A significant improvement in climbing ability was observed in flies treated with B. monnieri compared with untreated PINK1 mutant flies. However, a significant decrease in climbing ability was observed in WT flies for the same herb. Centella asiatica also significantly decreased climbing ability in WT flies. No significant effects were observed with any of the other herbs in either PINK1 or WT flies compared with untreated flies.

Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin.

High temperature requirement A2 (HtrA2/Omi) is a mitochondrial protease that exhibits proapoptotic and cell-protective properties and has been linked to Parkinson's disease (PD). Impaired mitochondrial function is a common trait in PD patients, and is likely to play a significant role in pathogenesis of parkinsonism, but the molecular mechanisms remain poorly understood. Genetic studies in Drosophila have provided valuable insight into the function of other PD-linked genes, in particular PINK1 and parkin, and their role in maintaining mitochondrial integrity. Recently, HtrA2 was shown to be phosphorylated in a PINK1-dependent manner, suggesting it might act in the PINK1 pathway. Here, we describe the characterization of mutations in Drosophila HtrA2, and genetic analysis of its function with PINK1 and parkin. Interestingly, we find HtrA2 appears to be dispensable for developmental or stress-induced apoptosis. In addition, we found HtrA2 mutants share some phenotypic similarities with parkin and PINK1 mutants, suggesting that it may function in maintaining mitochondrial integrity. Our genetic interaction studies, including analysis of double-mutant combinations and epistasis experiments, suggest HtrA2 acts downstream of PINK1 but in a pathway parallel to Parkin.