Analysis of circulating protein aggregates as a route of investigation into neurodegenerative disorders

• DOI: 10.1093/braincomms/fcab148
• Publication Date: 2021-07-05T19:13:56Z
• Authors: Rocco Adiutori; Fabiola Puentes; Michael Bremang; Vittoria Lombardi; Irene Zubiri; Emanuela Leoni; Johan Aarum; Denise Sheer; Simon McArthur; Ian Pike; Andrea Malaspina
• Keywords: Proteostasis; Proteome; Neurofilament; Proteolysis

Plasma proteome composition reflects the inflammatory and metabolic state of organism can be predictive system-level organ-specific pathologies. Circulating protein aggregates are enriched with neurofilament heavy chain-axonal proteins involved in brain aggregate formation recently identified as biomarkers fatal neuromuscular disorder amyotrophic lateral sclerosis. Using unbiased proteomic methods, we have fully characterized content neuronal circulating from sclerosis patients healthy controls, reference to composition. We also investigated aggregation propensity, stability proteolytic digestion toxicity for endothelial cell lines. separated by ultracentrifugation visible electron-dense macromolecular particles appearing either large globular or small filamentous formations. Analysis mass spectrometry revealed that obtained proteasome system, possibly reflecting underlying basis dysregulated proteostasis seen disease, while those controls show enrichment metabolism. Compared whole human proteome, within distinct chemical features which appear dependent on tissue fluid origin not health status. Neurofilaments' two high-mass isoforms (460 268 kDa) showed a strong differential expression compared control aggregates, aggregated chain was partially resistant enterokinase proteolysis patients, demonstrated immunoreactive bands at 171 31 kDa fragments digested samples. Unbiased proteomics total 4973 were commonly detected brain, including 24 expressed genes associated Interestingly, 285 (5.7%) regulated (P < 0.05) present biochemical pathways linked disease pathogenesis aggregation. Biologically, both had more pronounced effect viability hCMEC/D3 PC12 cells immunoglobulins extracted same plasma Furthermore, exerted toxic than lines lower concentrations (P: 0.03, cases). This study demonstrates significantly representative pathology potential source therapeutic targets this incurable disorder.