Commentary: BAG3 as a Mediator of Endosome Function and Tau Clearance. (10th May 2023)

• Record Type: Journal Article
• Authors: Lin, Heng; Deaton, Carol A.; Johnson, Gail V.W.
• Is Part Of: Neuroscience. Volume 518(2023)
• Page Start: 4
• Page End: 9
• Publication Date: 2023-05-10
• Subjects: AD Alzheimer's disease -- APP amyloid protein precursor protein -- BAG3 Bcl-2-associated anthogene 3 -- CBD Corticobasal Degeneration -- CMA chaperone-mediated autophagy -- GEF guanine nucleotide exchange factor -- ILV intraluminal vesicle -- MVBs multi-vesicular bodies -- PSP Progressive Supranuclear Palsy; BAG3 -- tau -- ESCRT -- Rab35 -- Arf6 -- TBC1D10B; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2022.05.002
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: BAG3 is a multidomain protein that plays a key role in maintaining neuronal proteostasis. BAG3 plays an important role in mediating vacuolar-dependent degradation of tau. In the BAG3 interactome, the endosome-lysosome pathway was the most over-represented. BAG3 regulates the recruitment of ESCRT-0/Hrs, and thus tau, to the endosome in part by interacting withTBC1D10B to attenuate the inactivation of Rab35. BAG3 is a key regulator of vacuolar system and therefore is an important factor in the development of tau pathology. Abstract: 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.