Pathological Disulfide bond Crosslinking: Molecular Insights into Amyloidogenesis and Diseases Progression.

Abstract

Amyloidogenesis is a complex process in which normally soluble proteins misfold and assemble into β-sheet-rich aggregates known as amyloid fibrils. This pathological process is implicated in a broad range of diseases, including neurodegenerative disorders and systemic amyloidosis. Recent studies indicate that disulfide-crosslinking plays a central role in promoting protein aggregation by stabilizing misfolded intermediates. This review highlights the cellular pathways leading to abnormal disulfide bond formation and examines their impact on disease progression. Additionally, we discuss how disulfide-crosslinked oligomeric species resist degradation, overwhelm proteostasis systems, and serve as precursors for amyloid fibrils. By understanding the role of disulfide crosslinks in protein aggregation, we gain insights into amyloid pathogenesis and identify potential therapeutic targets for intervention.