Mapping Parkinson’s Disease Progression through Deep Plasma Proteomics and Functional Genomics
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Parkinson’s disease (PD) is a progressive neurodegenerative disorder lacking disease-modifying therapies, and its clinical management is limited by the absence of accessible biomarkers for tracking disease progression and treatment response. To map these complex disease trajectories, we implemented an ultra-deep plasma proteomics workflow integrating Mag-Net extracellular vesicle enrichment with Orbitrap Astral mass spectrometry to profile longitudinal samples from PD patients. This approach quantified 6,481 plasma proteins at unprecedented depth in PD studies, revealing distinct signatures directly associated with disease duration and dopaminergic therapy exposure. Candidate biomarkers were subsequently validated in an independent cohort using ELISA, demonstrating robust predictive utility in AI-driven prediction models. To uncover the mechanistic drivers underlying these systemic changes, we intersected our proteomic data with novel proteome-wide gene overexpression perturbation screens designed to identify regulators of alpha-synuclein pre-formed fibril (PFF) uptake and PFF-induced neuronal toxicity. Finally, an integrative network analysis combining three independent proteome-wide assays revealed that key pathological hubs, such as CD14, IFNG, and PLAT, are targets of currently approved pharmacological agents. Collectively, these findings provide a comprehensive, systems-level map for PD biomarker discovery and highlight druggable pathways to advance precision medicine strategies.
Authors: Ji-sun Kim, Chanhee Jeong, Maria Seo-Hyun Kim, Hyeyeon Kim, Seungmin Lee, Kyeong Beom Jo, Wen Luo, Irina Shlaifer, Su Hyeon Ha, Saba Sane, Kyung Ah Woo, Emma Lee, Youngjin Lee, SooYeon Chae, Jisu Han, Atina G. Cote, JongHyun Seo, Gunwoo Park, Myungjin Lee, Gyurie Lee, Nidhi Sahni, Jung-Hyun Choi, Ji-Hwan Park, David E. Hill, Hunsang Lee, Kenneth A. Matreyek, Stefanie N. Kairs, Blake L. Tsu, Sangtae Kim, Christopher A. Barnes, Jean-François Trempe, Janusz Rak, Jung Hwan Shin, Thomas M. Durcan, Ki-Jun Yoon, Dae-Kyum Kim, Han-Joon Kim
Institutions: Research Institute of the McGill University Health Centre, Seoul National University, Seoul National University Hospital, Korea Advanced Institute of Science and Technology, McGill University, Montreal Neurological Institute and Hospital, Yale University, Korea University, University of Toronto, Donnelly Centre for Cellular and Biomolecular Research, Ajou University, University of Arizona, Baylor College of Medicine, Chungbuk National University, Harvard University, Dana-Farber Cancer Institute, Case Western Reserve University, McGill University Health Centre, Institut du cancer Rosalind & Morris Goodman, The Montreal General Hospital Foundation
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7125608279