On protein quality control, myofibrillar myopathies, and neurodegeneration

Proteins are the building blocks of cells and need to be folded into pre-determined 3-dimensional shapes in order to fulfil their functions. In order to control the folding states of its proteins, the cell has developed a special network of proteins. Chaperones, of which humans have over 100 different ones, are central to this protein quality control (PQC) network and support the folding or degradation of proteins. Several age-related neurodegenerative diseases (e.g. Alzheimer’s, Parkinson’s, and Huntington’s disease) and (cardio)myopathies are hall-marked by protein aggregates that imply a failure of the PQC network.

In this thesis, we studied how different chaperones handle the different proteins causing these ‘protein aggregation’ diseases. We focus on 2 specific members, DNAJB6 and BAG3, which are required for the input and output of proteins to the central PQC regulator Hsp70, respectively.

We show that DNAJB6 is particularly capable of protecting neurons from huntingtin aggregation, even when up-regulated in non-neuronal cells, like astrocytes, suggesting a new mode of cell-non-autonomous neuronal protection.

Mutations in DNAJB6 and BAG3 themselves actually cause aggregation diseases in human. We focus on a BAG3-mutation that is associated with a severe myofibrillar myopathy in children and show that this mutation leads to a subtle defect in the output of HSP70-handled clients and a subsequent rapid, progressive collapse in PQC.

Our data show the importance of fine-tuning PQC to maintain cellular fitness and support healthy aging.