The autosomal deubiquitylase Trabid drives sex-divergent neurodegeneration in Drosophila

Risk of neurodegeneration including late onset Alzheimer’s and Parkinson’s disease is linked to aberrant ubiquitylation and accumulation of non-degraded proteins in brain cells. A glial network of innate immune genes modulates inflammatory responses to such protein deposition. However, vulnerability differs between the sexes. Here, we show that the Drosophila homologue of the human deubiquitylase Trabid has the same enzymatic activity as its human counterpart and aligns the sex-specific aspects of neurodegenerative phenotypes with changes in ubiquitylation and inflammatory activity. In flies, an enzymatically null Trabid ( trbd C518A ), caused sex-specific changes in locomotion, sleep patterns, brain histology and ultimately, lifespan. While both sexes were affected, locomotor and lifespan deficits were more severe in male flies. When NF-κB-related antimicrobial gene expression was suppressed in male trbd C518A glia, locomotion defects and lifespan reduction were rescued. Analysis of sex-specific changes in whole brain ubiquitinome, proteome enrichment profiles and in vitro pull downs, identified the stress protein Hsc70-4 as neuroprotective in females and a direct target of Trabid. Our results indicate that in a simpler brain, Trabid underscores sex dimorphism in disease neurology by controlling the balance of ubiquitylation.