Chaperones, protein homeostasis & protein aggregation diseases

Proteins are the functional molecules of cells and have to be folded into a specific three-dimensional structure. Besides being non-functional, non-folded proteins can easily clump together and form aggregates that can cause disease (e.g. Parkinson’s disease and Huntington’s disease). To avoid this, cells contain special sets of proteins called Heat Shock Proteins (HSPs) that prevent aggregates formation in a defence network called the protein quality control network. This thesis is about how this protein quality control network functions and plays a role in human diseases.
Misfolded proteins that can no longer be (re)folded, require degradation. We found that BAG proteins as regulators of Hsp70 which recognise the aberrant proteins, “decide” which system to use for protein degradation. For instance, BAG1 directs Hsp70 to deliver its clients to proteasomes that degrades soluble proteins. When this system is impaired, cells make more BAG3 that now directs Hsp70 to deliver the aberrant proteins to autophagosomes that also degrades protein aggregates. Interestingly, genetic mutations in BAG3 that cause heritable heart muscle diseases impair this BAG3 function, explaining why this mutation causes disease. For a heritable form of Parkinson’s disease, we identified a subset of small HSPs (called HSPB family) that can protect against the formation of toxic aggregates. Both the actions of BAGs and HSPBs do not require that Hsp70 levels have to be altered, which is of importance as elevating Hsp70 levels can increase the risk for cancer. Targeting BAG3 or HSPBs may thus be of potential usage in protein aggregation diseases.