To characterize the biology underlying hereditary spastic paraplegias (HSPs), which are a heterogeneous group of neurodegenerative disorders, Novarino et al. carried out exome sequencing of cases and controls from 55 HSP-affected families. They found genetic variants in 14 genes previously associated with HSP, as well as variants in 15 novel genes. The products of these genes were used to seed a protein–protein interaction network, which revealed key roles for endosomal trafficking and purine metabolism in HSP aetiology. Furthermore, the network uncovered additional HSP candidate genes and biological connections to other neurodegenerative diseases.