Plasma Proteome Profiling Reveals Inflammation Markers and Tafamidis Effects in V30M Transthyretin Polyneuropathy

Transthyretin (TTR) variant (V30M) polyneuropathy (ATTRv-PN) is a progressive systemic amyloidosis caused by transthyretin aggregation, leading to a variety of debilitating manifestations, including neuropathy and cardiomyopathy. We investigated the plasma proteome of heterozygotic V30M TTR asymptomatic carriers and heterozygotic V30M ATTRv-PN patients (before and after tafamidis treatment) versus WT TTR healthy control plasma using an organic solvent-induced shift in solubility assay to identify biosignatures for disease progression and therapeutic response. We identified many proteins, including TTR, apolipoproteins, ceruloplasmin, and proteins with functions in innate immunity that displayed changes in either their abundances or their sensitivity to precipitation. Elevated oxidative modifications of TTR and APOE in ATTRv-PN patients suggest a role for oxidative stress in disease pathogenesis/progression. Tafamidis treatment mitigated these pathology-associated changes, suggesting that alleviating proteotoxic stress impacts these other pathways. Although our study was limited to a Portuguese cohort, these findings nevertheless provide a comprehensive plasma proteomic profile of V30M ATTRv-PN patients, V30M TTR carriers, and tafamidis-treated ATTRv-PN patients over up to 60 months; provide insights into ATTRv-PN pathophysiology; identify potential biomarkers for disease progression and therapeutic response; and highlight the utility of proteomics in advancing personalized treatments for amyloidosis.