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 (trbdC518A), 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 trbdC518A 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.

We would like to thank Dr Srishti Arora, Dr Anissa Kempf and Professor Gero Miesenböck who provided help and equipment for Drosophila activity monitoring. We thank the Discovery Proteomics Facility led by Roman Fischer and Iolanda Vendrell for expert help with mass spectrometry analysis. A.P.F. and B.M.K. were supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 2018-I2M-2-002) and by Pfizer.

I.D. and J.Y.L. were supported by Wellcome Investigator Award (209412), P.E. was supported by a Medical Research Council (MRC) Career Development Fellowship (MR/R008582/1), A.V. was supported by a Leverhulme Trust Research Project Grant (RPG-2022-202) and an European Union’s H2020 R&I Programme Grant (No. 857524), P.L. was supported by the Royal Society (IEC\NSFC\201298), the EP Abraham Cephalosporin Trust Fund (CF338) and the John Fell Fund (0010611). Department of Biochemistry, University of Oxford South Parks Rd, Oxford, UK Jingnu Xia, Jeffery Y. Lee, Emre Gumusdis, Ilan Davis, Paul Elliott & Petros Ligoxygakis Department of Basic and Clinical Neurosciences, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 5 Cutcombe Road, London, UK Chinese Academy of Medical Sciences Oxford Institute & Nuffield Department of Medicine, University of Oxford, Oxford, UK Adán Pinto-Fernández & Benedikt M.

Kessler Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford Old Road Campus, Oxford, UK Adán Pinto-Fernández, Andreas Damianou & Benedikt M. Kessler MIA-Portugal, Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.