Kavli Affiliate: Becky Carlyle
| Authors: Helen A. Jolly, Paula Seghers, Kaleah Balcomb, Amelia J. Smith, Laura Pearson, Ishan Agrawal, Bethany Geary, David A. Bennett, Thomas Wisniewski, Stephanie L. Fowler, Eleanor Drummond, Oliver M. Crook and Becky C. Carlyle
| Summary:
Proteome-wide analyses of human tissue have transformed our understanding of disease, but provide limited insight into protein localisation, a functionally informative dimension of the proteome. In Alzheimer’s disease, amyloid-β and tau exhibit aberrant localisation, yet whether spatial reorganisation extends proteome-wide has remained inaccessible to abundance-based proteomics. Here, we develop comparative subcellular proteomics applied to dorsolateral prefrontal cortex from 75 individuals spanning the Alzheimer’s disease-resilience spectrum, modelling protein localisation across disease. We identify 217 disease-associated localisation shifts enriched for endolysosomal function, intracellular trafficking, and RNA processing, and resolve tau proteoforms within insoluble aggregates. Our strongest localisation candidates show only modest differences in whole-tissue abundance, highlighting disease biology inaccessible to conventional proteomics. We validate co-localisation of CSNK1A1 with pathological tau and identify an unexpected neuronal localisation pattern for SCAI, a cancer-associated protein not previously characterised in human brain, highlighting the discovery potential of subcellular proteomics in tissue.