ProjectsChemical interference with the activity of the human Hsp70 chaperone machinery in the disaggregation of α-synuclein amyloid fibrils
The aggregation of aberrant proteins into amyloid fibrils is a hallmark of many neurodegenerative diseases including Parkinson’s disease (PD). Their high stability renders amyloid fibrils challenging substrates to the cellular protein quality control machinery. However, we showed earlier that the human Hsp70 chaperone with its co-chaperones DNAJB1 and Hsp110 can dissolve preformed amyloid fibrils of PD-linked α-synuclein in vitro (1) and recently we revealed the molecular mechanism of this process (2, 3). These mechanistic insights into the essential pre-requisites to amyloid disaggregation by the Hsp70 system now provide the basis for a novel avenue towards therapeutic intervention in neurodegeneration. This approach is of particular interest because rather than preventing the initial pathological aggregation of proteins into amyloid fibrils which pre-requisites very early intervention in the disease progression, our approach targets species formed at a later timepoint and intends to neutralize their negative effects allowing for a wider therapeutic window. We have developed robust in vitro assays that are able to detect amyloid binding and disaggregation activity of the Hsp70 chaperone system and we are now performing high throughput screening of chemical compound libraries.
(1) Gao, X., Carroni, M., Nussbaum-Krammer, C., Mogk, A., Nillegoda, N.B., Szlachcic, A., Guilbride, D.L., Saibil, H.R. Mayer, M.P., Bukau, B*. Human Hsp70 Disaggregase Reverses Parkinson's-Linked α-Synuclein Amyloid Fibrils. Mol. Cell (2015) 59, 781-793.
(2) Wentink, A.S.*, Nillegoda, N.B., Feufel, J., Ubartaitė, G., Schneider, C.P., De Los Rios, P., Hennig, J., Barducci, A., Bukau, B.* Molecular dissection of amyloid disaggregation by the human Hsp70 chaperone, Nature (2020), in press.
(3) Faust, O., Abayev-Avraham, M., Wentink, A.S., Maurer, M., Nillegoda, N.B., London, N., Bukau, B.*, Rosenzweig, R.* Hsp40s employ class-specific regulation to drive Hsp70 functional diversity, Nature (2020), in press.