BAG6 Prevents the Aggregation of Neurodegeneration-Associated Fragments of TDP43

Abstract

Neurodegeneration is associated with the aggregation of proteins bearing solvent-exposed hydrophobicity. The accumulation of such proteins results from their proteolytic cleavage and/or misfolding as well as defects in protein quality control mechanisms that otherwise scrutinize and eliminate aberrant proteins. Here, we found that the Bcl-2 associated athanogene 6 (BAG6), a component of a multi-subunit molecular chaperone complex, functions as a sensor of proteolytic fragments bearing solvent-exposed hydrophobicity and prevents their intracellular aggregation. Specifically, we show that BAG6 maintains the solubility of disease-associated C-terminal fragments of the TAR DNA‐binding protein 43 (TDP43) and prevents their oligomerization. In addition, BAG6 facilitates the ubiquitylation of TDP43 fragments by recruiting the Ub-ligase, Ring finger protein 126 (RNF126). Authenticating its role in preventing aggregation, we found that TDP43 proteolytic fragments form intracellular aggregates in the absence of BAG6. Finally, we found that BAG6 effects are not limited to proteolytic fragments of TDP43 and likely play a general role in preventing intracellular aggregation associated with neurodegeneration.