Copper's dual influence: Self-assembly and anti-amyloidogenic activity of monomeric transthyretin

Disturbances in metal ion homeostasis are linked to neurodegenerative diseases associated with amyloidogenic peptides or proteins, although the precise molecular mechanisms underlying the pathological connections between metal ions and amyloid-forming species remain elusive. Here we report the discovery of how copper affects the self-assembly and anti-amyloidogenic activity of monomeric transthyretin (M-TTR), the aggregation-prone species originating from the native homotetrameric TTR. Our findings reveal that Cu(II) binding to M-TTR induces covalent adduct formation and oxidative modifications, leading to the enhancement of its aggregation and apoptosis-mediated cytotoxicity. Moreover, Cu(II) alters the interaction between M-TTR and amyloid-beta (Abeta), a pathogenic factor in Alzheimer’s disease, and, consequently, affects M-TTR’s ability to modulate the aggregation and toxicity profiles of Abeta. Our study demonstrates the effects of copper on the pathological properties of M-TTR, which sheds light on the contribution of copper to the pathologies of neurodegenerative disorders linked to aggregation-prone proteins.