Lessons from Fruit Fly Models for PolyQ Neurodegenerative Disorders

Polyglutamine (polyQ) diseases, resulting from a dynamic expansion of glutamine repeats in a polypeptide, are a class of genetically inherited, late-onset neurodegenerative disorders which, despite wide expression of the mutated gene in brain and other tissues, affect defined subpopulations of neurons in a disease-specific manner. This presentation will review the advantages of modelling these neurodegenerative diseases in Drosophila, and the insights obtained. Studies with the fruit fly models have successfully identified a variety of genetic modifiers, and have helped to further our understanding of some of the molecular events that follow expression of the abnormal polyQ proteins. Expression of the mutant polyQ proteins causes, as a consequence of intra-cellular and inter-cellular networking, mis-regulation in the sensitive neurons at multiple points, such as during transcriptional regulation, post-transcriptional regulation, cell signalling, protein quality control (protein folding and degradation networks), and axonal transport, resulting ultimately in cell death. The diversity of genetic modifiers of polyQ toxicity, identified through extensive genetic screening in the fruit fly and in other models, clearly reflects a complex network effect of the presence of the mutated protein. Such a network effect poses a major challenge for therapeutic applications.