Copper(II) prevents neurokinin B functional amyloid formation and disassembles preformed fibrils

Jayawardena BM and Jones CE

School of Science and Health, Western Sydney University, Locked bag 1797, Penrith, NSW, 2751.

Neurokinin B (NKB) belongs to a family of neuropeptides that have diverse roles in cognition, neuroprotection and neuroinflammation. NKB has a key role in reproduction and consequently is found in high concentrations in hypothalamic neurons that descend into the pituitary gland. Some evidence suggests NKB is packed into secretory granules as an amyloid, termed ’functional amyloid’, which is thought to allow high peptide concentrations to be achieved in the granule. Several neuropeptides and hormones are known to form functional amyloids but interact with receptors in the monomeric form. The mechanisms underlying the disassembly of the amyloid are not clear, although dilution, pH and ionic strength are all thought to contribute. NKB is known to bind copper with reasonably high affinity. Metal binding does not affect receptor activation and it has remained unclear as to why NKB binds copper. In this work we use a variety of biophysical techniques to show that copper(II) has an important role in NKB fibrillogenesis. At stoichiometric concentrations, copper will completely inhibit formation of NKB fibrils and is the only biological metal that can achieve this. Importantly, the metal can also promote disassembly of preformed fibrils. These results will be discussed in the context of NKB’s function and compared to the role of metals in amyloidogenic neurodegenerative diseases.