Commentary: BAG3 as a Mediator of Endosome Function and Tau Clearance

Tauopathies are a group of heterogeneous neurodegenerative conditions characterized by the deposition of abnormal tau protein in the brain. The underlying mechanisms that contribute to the accumulation of tau in these neurodegenerative diseases are multifactorial; nonetheless, there is a growing awareness that dysfunction of endosome-lysosome pathways is a pivotal factor. BCL2 associated athanogene 3 (BAG3) is a multidomain protein that plays a key role in maintaining neuronal proteostasis. Further, recent data indicate that BAG3 plays an important role in mediating vacuolar-dependent degradation of tau. Overexpression of BAG3 in a tauopathy mouse model decreased pathological tau levels and alleviated synapse loss. High throughput screens of BAG3 interactors have identified key players in the vacuolar system; these include clathrin and regulators of small GTPases. These findings suggest that BAG3 is an important regulator of endocytic pathways. In this commentary, we discuss the potential mechanisms by which BAG3 regulates the vacuolar system and tau proteostasis.