Objective: This study’s objective was to discover novel plasma protein biomarkers related to progression and treatment response with a longitudinal PD cohort using an integrated approach of advanced proteomics and functional genomics.

Background: Parkinson disease (PD) is a progressive neurodegenerative disorder with limited therapeutic options. The lack of effective treatments stems partly from the absence of robust biomarkers.

Method: We combined Orbitrap Astral mass spectrometry with Mag-Net, a novel method for depleting abundant plasma proteins and enriching extracellular vesicles. This platform was applied to a longitudinal cohort of 10 PD patients with paired plasma samples collected at diagnosis and after 2-7 years of disease progression with treatment. We used dimensionality reduction and multivariate analysis to identify protein signatures. [figure 1] We also performed a functional genomics screen using a proteome-wide overexpression library to identify genes that modulate alpha-synuclein pre-formed fibril uptake.

Results: Our proteomics workflow identified an unprecedented 6,485 plasma proteins. Dimensionality reduction revealed distinct proteomic signatures that separated samples based on disease stage, a separation not possible with conventional proteomic depth. Multivariate analysis identified disease progression and levodopa equivalent daily dose (LEDD) as the primary factors influencing longitudinal proteomic changes. [figure 2] Functional genomics screening identified novel regulators of PFF uptake, including DERL1 (decreased PFF uptake) and NUDC (increased PFF uptake). [figure 3]

Conclusion: This study demonstrates an integrated approach to identify new biomarkers and provide insights into PD. The identified biomarkers associated with both disease progression and levodopa treatment have translational potential in both disease monitoring and drug development. These findings lay the groundwork for developing precision diagnostics and personalized therapeutic strategies for Parkinson’s disease.​

Protein signature from plasma proteins

Progression-related protein biomarkers

ASyn PFF uptake related cell viability assay

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MDS Abstracts - https://www.mdsabstracts.org/abstract/uncovering-parkinson-disease-progression-biomarkers-with-plasma-proteomics-and-functional-genomics/