Valosin-containing protein (VCP/p97) mutations are associated with multisystem proteinopathy (MSP), a rare autosomal dominant disorder characterized by progressive muscle weakness, bone disease, and neurodegenerative manifestations such as ALS/FTD. Despite advances in understanding the genetic basis of VCP-related MSP, the molecular mechanisms underlying disease pathogenesis remain incompletely characterized. Plasma biomarkers may provide insights into disease-specific protein dysregulation and potential therapeutic targets. To identify differentially expressed plasma proteins in VCP mutation carriers compared to healthy controls,
we performed a case-control proteomics study using plasma samples from 18 VCP mutation carriers and 18 age- and sex-matched healthy controls in collaboration with Cure VCP Disease, Inc. Protein expression profiling was conducted using Nucleic Acid Linked Immuno-Sandwich Assay, a highly sensitive quantitative proteomics platform. We identified 41 differentially expressed proteins in the plasma of VCP mutation carriers compared to controls. Of these, 35 proteins were upregulated, and 6 proteins were downregulated in the mutation group. These dysregulated proteins represent potential biomarkers for VCP-related MSP and may reflect underlying pathophysiological processes including protein homeostasis dysregulation, inflammatory responses, and metabolic alterations associated with VCP dysfunction. This study provides the first comprehensive plasma proteomic profile of VCP mutation carriers, revealing significant protein dysregulation that may contribute to disease pathogenesis and establish a foundation for biomarker development and therapeutic target identification in VCP-related multisystem proteinopathy. Further validation studies are warranted to elucidate their roles in disease progression and their utility as clinical biomarkers.