Behavioral screening defines three molecular Parkinsonism subgroups in <i>Drosophila</i>

Abstract

Abstract Parkinsonism is defined by motor dysfunction, but the specific upstream molecular causes of these clinical symptoms can vary widely. We hypothesize that these causes converge onto a limited number of core cellular pathways. To investigate this, we created a new collection of 24 genetically very well-controlled animal models of familial forms of parkinsonism. Using unbiased behavioral screening and machine learning we identified three clusters of mutants that converge on (1) mitochondrial function; (2) retromer/vesicle trafficking; and (3) proteostasis/autophagy. Genes within each cluster have a similar genetic interaction profile and compounds that target specific molecular pathways ameliorate dopaminergic neuron dysfunction in a cluster-specific manner. This suggests that familial parkinsonism can be stratified into three broad functional groups and our findings pave the way for targeted biomarker discovery and drug development.