Pan-neurodegeneration proteomics reveals disease subtypes and molecular signatures.
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Shrestha Him K, Sun Huan, Yarbro Jay M, Lee DongGeun, Liu Danting, Wang Erming, McReynolds Meghan, Zhang Nan, Xie Boer, Yang Shu, Yu Kaiwen, Poudel Suresh, Li Yuxin, Yuan Zuo-Fei, Kong Dehui, Wang Minghui, Wang Zhen, Niu Mingming, Wang Hong, Zaman Masihuz, Wang Ju, Vanderwall David R, Sun Yu, Wu Zhiping, Chen Ping-Chung, Bai Bing, High Anthony A, Faura Júlia, Liu Chunyu, Bennett David A, Johnson Erik C B, Seyfried Nicholas T, Levey Allan I, Haroutunian Vahram, Serrano Geidy E, Beach Thomas G, DeTure Michael, Kanekiyo Takahisa, Petersen Ronald C, Bu Guojun, McLean Pamela J, Dickson Dennis W, Rademakers Rosa, Yu Gang, Wang Xusheng, Zhang Bin, Peng Junmin
Аннотация
Neurodegenerative diseases (NDs) pose clinical challenges due to their complexity and molecular heterogeneity. Here, we present a pan-neurodegeneration atlas (PanNDA) from multilayer, deep proteomic analysis of 2,279 human brain samples spanning 6 major NDs: Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal lobar degeneration with TDP-43 pathology, progressive supranuclear palsy with tau pathology, vascular dementia, and Parkinson's disease. PanNDA integrates data from whole proteome, detergent-insoluble proteome, and posttranslational modifications (phosphorylation and ubiquitination), enabling intra- and inter-disease comparisons. Intra-disease analyses uncover distinct molecular subtypes (e.g., three in AD and four in LBD), reveal dysregulated pathways, and prioritize top-ranked proteins. Inter-disease comparisons identify shared alterations in NDs, such as GPNMB in microglial and lysosomal activation and NPTX2 in synaptic regulation, alongside disease-specific changes and hub regulators within protein networks. Overall, PanNDA provides a systems-level framework for understanding ND mechanisms and serves as a foundational resource that is accessible via an interactive website: https://penglab.shinyapps.io/pannda.