Population-scale subcellular proteomics reveals intracellular remodelling across the Alzheimer's disease-resilience spectrum
Jolly, H. A.; Seghers, P.; Balcomb, K.; Smith, A. J.; Pearson, L.; Agrawal, I.; Geary, B.; Bennett, D. A.; Wisniewski, T.; Fowler, S. L.; Drummond, E.; Crook, O. M.; Carlyle, B. C.
Show abstract
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-{beta} 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.
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