In Situ Global Structural Proteome Analysis Identifies Potential Biomarkers for Parkinson's Disease.

Abstract

Limited proteolysis-coupled mass spectrometry (LiP-MS) is a recently developed approach for the global identification of structural proteome alterations affecting protein functions, including protein misfolding, conformational changes, binding of small molecules, and protein–protein interactions.1 Through identifying protein structural changes, this technique can provide insights into pathological conditions such as Parkinson's disease (PD) over conventional protein abundance measures.1 PD represents an ideal model for testing the performance of LiP-MS due to the fact that its pathophysiology is closely linked to protein aberrations.2 Mackmull and colleagues have recently investigated the potential of LiP-MS for detecting structural proteome alterations in PD.3 Using cerebrospinal fluid (CSF) samples from a cohort of 52 PD patients and 51 age- and sex-matched healthy subjects, the researchers identified a total of 76 structurally altered proteins in PD patients compared to controls. These proteins were enriched in processes misregulated in PD, including synapse-related functions, indicating a potential link between such proteins and disease pathology. This was further supported by the finding that 16 out of the 76 proteins identified in CSF PD samples were also structurally altered in PD brain samples compared to controls. Interestingly, three of these proteins (AAK1, CYRIB, and APOE) were previously linked to PD risk or progression in GWAS studies. Investigating the reliability of the 76 structurally altered proteins as disease biomarkers, they demonstrated higher efficiency in discriminating PD patients from controls than protein abundance measures. The performance of the 76 proteins was found comparable and complementary to the oligomeric/total α-synuclein ratio. The combination of the LiP model with the ratio of oligomeric/total α-synuclein classified individuals with PD with better performance (91% accuracy) than either measure alone (75% accuracy).3 Overall, this study highlighted the potential of global proteome structural alterations as PD biomarkers with high sensitivity and specificity. LiP-MS represents a promising technique for analysis of proteome conformational changes directly in biofluids of participants in clinical cohorts, following a simple protocol that is applicable in a standard biochemistry laboratory.1 However, despite the remarkable findings of this work, further studies are needed to validate the utility of the identified structurally altered proteins as disease biomarkers and decipher their implication in PD pathogenesis. This work was supported in part by the Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Against Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (https://gp2.org). For a complete list of GP2 members see https://gp2.org. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique. M.A.H.: 1A, 1B, 2A, 2B I.E.: 1A, 1B, 2A, 2B Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.