Oligomeric forms of various aggregation-prone amyloid forming peptides are considered to be especially neurotoxic and exist only transiently and in low abundance yet they cause damage before they eventually form fibrils The anti-amyloidogenic human chaperone DNAJB6 can capture such oligomeric forms (Österlund et al 2020) by strong binding, as here outlined (above) for an amyloid-β (Aβ) tetramer (white), to the peptide binding cleft at the center of the DNAJB6 dimer (blue). Image: Courtesy to Nicklas Österlund.

This is DNAJB6 - an early stage scavenger of amyloid peptides. A structure model (above) shows how DNAJB6 (grey) may form dimers in which there is a peptide-binding cleft lined with S/T-residues (pink) at the monomer-monomer interface and how DNAJB6 subunits are assembled into an oligomeric conformation. Sub-stoichiometric concentrations of DNAJB6 can suppress amyloid fibril formation by aggregation prone peptides such as poly Q (Månsson et al. 2014a) and Ab (Månsson et al. 2014b), through inhibition of the primary nucleation step (Arosio et al. 2016). This inhibition is dependent on a unique S/T-rich region (Månsson et al. 2018) lacking in most other DNAJ-proteins (Kampinga et al. 2019). Due to the side chains of the serine (S) and threonine (T) residues, this conserved S/T-rich region in DNAJB6 exposes hydroxyl groups in a possible peptide-binding cleft (Söderberg et al. 2018) making it possible to capture dangerous aggregation-prone peptides. DNAJB6 is an essential protein and knock-out mice die already in uteri due to failure in keratin turnover and placental development. We have shown in a mouse model for Huntington’s disease (R6/2) that brain-specific expression of DNAJB6 decreased symptoms and increased life-time, better than for any treatment tested previously with this disease model (Kakkar et al. 2016). Beneficial effect on dendrites in neural cells was detectable already before any aggregates or fibrils were detectable. We have shown that DNAJB6 can prevent fibril formation by poly Q, Ab, α-synuclein and IAPP that relate to Huntington’s, Alzheimer’s and Parkinson’s disease and diabetes, respectively.