The Pharmacology and Dual Role of Proteostasis in Amyloidoses

Cellular protein quality control comprises the ubiquitin proteasome system, autophagy, and molecular chaperones, which maintain proteostasis in healthy tissues. The failure of these cellular and molecular pathways, which normally safeguard the proteome, can cause and even exacerbate amyloidoses, the abnormal accumulation of proteins into amyloid fibrils that drive neurodegeneration. Amyloidoses can also damage peripheral organs; examples include light chain amyloidosis, cardiac amyloidosis, and renal amyloidosis. Restoring proteostasis and preventing protein aggregation is therefore an active area of research, with several promising strategies under investigation. Among these approaches, small-molecule modulators that restore proteostasis are attractive candidates because they may simultaneously rescue multiple quality control mechanisms and remodel aggregates to improve their accessibility to endogenous degradation pathways. Here, we propose that amyloid pathology disrupts multiple proteostasis pathways simultaneously, creating a feedforward cascade in which the breakdown of interconnected proteostasis networks drives progressive protein aggregation, which in turn propels proteostasis collapse. Pharmacological interventions targeting protein aggregation offer opportunity to rescue interconnected proteostasis networks, which could, in turn, cooperatively manage or eliminate pathogenic amyloid burden.