Metal ions as modulators of protein conformation and misfolding in neurodegeneration

Protein misfolding and conformational changes are a cornerstone of neurodegenerative diseases involving formation and deposition of toxic protein oligomers. Although mutations favor protein aggregation, physiological factors such as labile metal ions within the cellular environment are likely to play a role. Metal ions such as calcium, zinc and copper are key players in brain neurobiology, their homeostasis is altered in most neurodegenerative conditions and they are found within proteinaceous inclusions from patients. In this review we will elucidate the intricate interplay between protein (mis)folding and metal ions, discussing how metals modulate protein folding and influence protein energetics, with specific attention on conformational changes and structural fluctuations. In particular, the influence of metal ion dyshomeostasis during neurodegeneration and the effects of the unique physical and chemical properties at the synaptic environment will be discussed in the context of protein deposition. These interactions will be illustrated by specific examples of proteins involved in neurodegenerative diseases including α-synuclein, tau, superoxide dismutase 1, the prion protein and the amyloid-β peptide. With this approach we aim to systematize the effects of metal ions on protein conformers and illustrate pathways through which they modulate protein aggregation, under different conceptual mechanisms that bridge protein structure, metallochemistry and neurobiology.

► Metal ions play a decisive role in the regulation of protein function and folding but can also promote protein misfolding and aggregation. ► The main concepts concerning protein folding and dynamics, folding energetics and the role of metal ions in these processes are reviewed. ► High levels of labile metal ions in the synaptic milieu are likely to facilitate protein aggregation in neurodegenerative disorders. ► Many neurodegeneration-related proteins have structural disorder and share a pattern of promiscuous metal binding properties likely to dictate their protagonist role in aggregation. ► We systematize the roles of metals in proteins involved in major neurodegenerative conditions: α-synuclein, tau, SOD1, the prion protein and Aβ.