Behavioral screening defines the molecular Parkinsonism-related subgroups in Drosophila

Parkinson's disease (PD) and related familial Parkinsonism are 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 collection of 24 genetically well-controlled Drosophila models of familial forms of PD and related mono-genic forms of Parkinsonism. Using unbiased behavioral screening and machine learning we identify clusters of mutants that converge on (1) mitochondrial function; (2) retromer/vesicle trafficking and 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. Together, our data indicate that familial PD and related forms of Parkinsonism may fall into two broad functional groups, and may inform further work toward targeted biomarker discovery and therapeutic development.