Hsp104 redesigned to mitigate FUS and TDP-43 proteinopathies

Hsp104, a hexameric, disaggregase protein interacts with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated proteins but how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. In this paper, the researchers establish design principles for therapeutic Hsp104 variants.

By leveraging high-resolution structures of the Hsp104 disaggregase, they rationally engineer enhanced disaggregases with retuned Hsp70 collaboration and minimal off-target unfoldase activity.

These safely enhanced Hsp104 variants effectively mitigate FUS and TDP-43 proteinopathies in human cells.

https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01356-1

https://sciencemission.com/Hsp104-therapeutics