Bag3, also known as B-cell lymphoma 2-associated-athanogene 3, is a multi-domain protein and a member of the BAG family of co-chaperones. It plays a crucial role in multiple biological processes. It is directly involved in cellular protein quality control as a mediator for selective macroautophagy, and also modulates apoptosis, cytoskeleton dynamics, and cell survival [3,4,5,6]. It interacts with molecular chaperones like Hsp70, regulating their activities and nucleotide cycling [6].

In neurodegenerative disease models, astrocyte-specific Bmal1 deletion in mouse tauopathy or alpha-synucleinopathy models leads to astrocyte activation and increased Bag3 expression. This, in turn, enhances phagocytosis of αSyn and tau in a Bag3-dependent manner, and astrocyte Bag3 overexpression mitigates αSyn spreading in vivo. In humans, BAG3 is increased in AD patients and highly expressed in disease-associated astrocytes, suggesting its potential role in neurodegeneration [1]. In ischemic stroke models, BAG3 overexpression activates autophagy and inhibits apoptosis, protecting against cerebral ischemia/reperfusion and hypoxia/reoxygenation injury [2].

In conclusion, Bag3 is essential for maintaining protein homeostasis and is involved in key cellular processes like autophagy and apoptosis. Mouse models, including those with gene-specific deletions, have revealed its significance in neurodegenerative diseases and ischemic stroke, highlighting its potential as a therapeutic target in these disease areas.