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Pan-neurodegeneration proteomics reveals disease subtypes and altered molecular signatures in six neurodegenerative disorders

ABSTRACT: Neurodegenerative diseases (NDs) pose clinical challenges due to their complexity and molecular heterogeneity, limiting effective diagnosis and treatment. Here, we present an unprecedented multi-layered proteomic atlas of over 2,000 human brain samples spanning controls and six major NDs, including Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal lobar degeneration (FTLD), vascular dementia (VAD), Parkinson's disease (PD), and progressive supranuclear palsy (PSP). The profiling includes the whole proteome, detergent-insoluble aggregation-enriched proteome, and post-translational modifications of phosphorylation and ubiquitination. The atlas reveals distinct intra-disease and inter-disease proteomic signatures. The intra-disease analysis uncovers distinct molecular subtypes and dysregulated pathways within each ND, such as three AD subtypes and four LBD subtypes, independent of known pathological classifications. Inter-disease analysis identifies shared alterations in neuroinflammation and synaptic dysfunction and disease-specific alterations in protein aggregation, response to unfolded proteins and activation of developmental signaling. This large-scale proteomics study provides critical insights into ND mechanisms and offers a unique resource for future research.

INSTRUMENT(S): Orbitrap Exploris 480, Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Junmin Peng

PROVIDER: MSV000097496 | MassIVE | Wed Apr 02 08:53:00 BST 2025

SECONDARY ACCESSION(S): PXD062529

REPOSITORIES: MassIVE

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Pan-neurodegeneration proteomics reveals disease subtypes and altered molecular signatures in six neurodegenerative disorders

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