Project Details
Projekt
Chaperone remodelling of HTT exon-1 aberrant folding and association in condensation processes
Applicant
Professor Dr. Simon Ebbinghaus
Subject Area
Biochemistry
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 545039200
Aberrant folding, condensation and aggregation of the Huntingtin protein (HTT) is driven by an expansion of the polyQ tract in HTT exon-1. Different protein species of HTT exon-1, including aberrantly folded monomers, oligomers, fibrils and condensates have been identified in vitro and in vivo. However, our understanding of the formation and interconversion of these protein species as well as their toxicity is limited. Moreover, how cellular factors such as molecular chaperones influence these protein species is largely unclear, preventing the development of novel therapeutic interventions in polyQ expansion diseases. In this proposal we will focus on condensates as intermediate states on the pathway to pathological aggregates. We will investigate the aberrant folding and association of the HTT exon-1 monomers and how these molecular events promote condensation and fibrilization. With the obtained insights, we will next dissect how chaperones influence aberrant folding and association of the HTT exon-1 and how they interact with HTT exon-1 condensates. We will bring specific expertise and techniques (such as Fast Relaxation Imaging) to the FOR that will allow us to analyze the underlying kinetics of these molecular processes in living cells. Collaborative work in the context of the FOR will encompass complementary in vitro, in vivo and in silico studies, providing a much deeper mechanistic understanding of the role of chaperones and condensates in protein misfolding diseases.
DFG Programme
Research Units
