Bar-coding neurodegeneration: identifying subcellular effects of human neurodegenerative disease proteins using...

Genetic, biochemical and histological studies have identified a number of different proteins as key drivers of human neurodegenerative diseases. Although different proteins are typically involved in different diseases, there is also considerable overlap. Addressing disease protein dysfunction in an in vivo neuronal context is often time consuming and requires labor-intensive analysis of transgenic models. To facilitate the rapid, cellular analysis of disease protein dysfunction, we have developed a fruit fly (Drosophila melanogaster) adult leg neuron assay. We tested the robustness of 41 transgenic fluorescent reporters and identified a number that were readily detected in the legs and could report on different cellular events. To test these reporters, we expressed a number of human proteins involved in neurodegenerative disease, in both their mutated and wild-type versions, to address the effects on reporter expression and localization. We observed strikingly different effects of the different disease proteins upon the various reporters with, for example, Aβ^1-42 being highly neurotoxic, tau, parkin and HTT^128Q affecting mitochondrial distribution, integrity or both, and Aβ^1-42, tau, HTT^128Q and ATX1^82Q affecting the F-actin network. This study provides proof of concept for using the Drosophila adult leg for inexpensive and rapid analysis of cellular effects of neurodegenerative disease proteins in mature neurons.