Characterization of the myopathy associated BAG3 P209L mutation

Myofibrillar myopathy is a protein aggregate myopathy characterized by disintegration of the Z-disk and accumulation of protein aggregates. A dominant missense mutation (P209L) in the co-chaperone BAG3 has been associated with a severe early onset form of myofibrillar myopathy. The disease causing P209L mutation in BAG3 is located in it’s binding site for HSPB8 (IPV domain), suggesting it might alter a functional HSPB8-BAG3 interaction. Recently we showed that wildtype BAG3, in association with HSPB8 and HSP70, participates in prevention of misfolded protein aggregation through macro-autophagy. In cultured HEK293T-cells the BAG3 P209L mutant was found to be impaired in its ability to prevent polyQ aggregation. This, however occurs without major effects on binding to the BAG3-partners HSPB8 and HSP70. Just like wildtype BAG3, the BAG3 P209L mutant was able to enhance LC3 lipidation, suggesting that its effect on autophagy stimulation is not impaired. This was confirmed by the absence of direct effects of mutant BAG3 on autophagic flux, instead the mutant strikingly showed impairment in cargo-delivery. Our studies in Drosophila Melanogaster further substantiate the loss of function phenotype of BAG3 P209L as the main mechanism underlying BAG3 P209L-related myopathy.