s Drosophila Models of Proteinopathies: the Little Fly that Could

Alzheimer's, Parkinson's, and Huntington's disease are complex neurodegenerative conditions with high prevalence character-ized by protein misfolding and deposition in the brain. Considerable progress has been made in the last two decades in identifying the genes and proteins responsible for several human ‘proteinopathies’. A wide variety of wild type and mutant proteins associated with neu-rodegenerative conditions are structurally unstable, misfolded, and acquire conformations rich in ß-sheets (ß-state). These conformers form highly toxic self-assemblies that kill the neurons in stereotypical patterns. Unfortunately, the detailed understanding of the molecu-lar and cellular perturbations caused by these proteins has not produced a single disease-modifying therapy. More than a decade ago, sev-eral groups demonstrated that human proteinopathies reproduce critical features of the disease in transgenic flies, including protein mis-folding, aggregation, and neurotoxicity. These initial reports led to an explosion of research that has contributed to a better understanding of the molecular mechanisms regulating conformational dynamics and neurotoxic cascades. To remain relevant in this competitive envi-ronment, Drosophila models will need to expand their flexible, innovative, and multidisciplinary approaches to find new discoveries and translational applications.