Sex-specific deubiquitylation drives immune-related neurodegeneration in Drosophila

Risk of neurodegenerative disease such as late onset Alzheimer’s is linked to aberrant ubiquitinylation 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 deubiquitylase Trabid can align the sex-specific aspects of neurodegenerative phenotypes with changes in ubiquitylation and inflammatory activity. An enzymatically null Trabid in flies, caused sex-specific changes in locomotion, sleep patterns, brain histology and ultimately, lifespan. These changes were underscored by altered ubiquitin and proteome enrichment profiles and the same enzymatic activity as its human counterpart. When the sex-determination gene transformer was silenced in astrocytes or immunocompetent tissues, sex differences were significantly reduced. Our results indicate that Trabid underscores sex-specificity in disease neurology, by controlling the balance between ubiquitylation and inflammation.