DISCO-MS: Proteomics of spatially identified tissues in whole organs

ABSTRACT: Spatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. Liquid chromatography coupled to mass spectrometry (LC-MS) is emerging as a key technology for the unbiased characterization of proteins, the drivers of cellular function. Furthermore, recent advances in imaging, transcriptomics and proteomics allowed the analysis of spatially resolved RNA- and protein-profiles from thin tissue sections. However, so far, no method has allowed the unbiased mass spectrometry (MS)-based proteomics analysis of target tissues identified by unbiased imaging of whole organs in 3D. Here, we present DISCO-MS, a technology combining solvent-based tissue clearing, whole-organ imaging by light-sheet microscopy, automated image analysis powered by deep learning, and ultra-high sensitivity mass spectrometry. DISCO-MS yields qualitative and quantitative proteomics data indistinguishable from uncleared samples in both rodent and human tissue. DISCO-MS of the proteomes of axonal tracts with activated microglia after brain injury revealed known and novel biomarkers. We characterized individual initial amyloid beta plaques in the brains of a young familial Alzheimer's disease mouse model, determined the core proteome of these aggregates and highlighted compositional heterogeneity. DISCO-MS enables the image-guided identification of rare target tissues in intact biological systems followed by MS-based proteome analysis, providing new diagnostic and therapeutic opportunities for complex diseases including neurodegeneration.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Heart, Brain, Lung

SUBMITTER: Mario Oroshi  

LAB HEAD: Matthias Mann

PROVIDER: PXD025316 | Pride | 2025-11-27

REPOSITORIES: Pride