Department of Anesthesiology and Perioperative Medicine, University of Rochester, 601 Elmwood Ave, Box 604, Rochester, NY 14642, USA.
Department of Anesthesiology and Perioperative Medicine, University of Rochester, 601 Elmwood Ave, Box 604, Rochester, NY 14642, USA.
Neuroscience. 2023 May 10;518:4-9. doi: 10.1016/j.neuroscience.2022.05.002. Epub 2022 May 10.
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.
tau 病是一组异质性神经退行性疾病，其特征是大脑中异常 tau 蛋白的沉积。导致这些神经退行性疾病中 tau 积累的潜在机制是多因素的；尽管如此，人们越来越意识到内体溶酶体途径的功能障碍是一个关键因素。BCL2 相关抗凋亡基因 3（BAG3）是一种多功能蛋白，在维持神经元蛋白质平衡方面发挥着关键作用。此外，最近的数据表明，BAG3 在介导 tau 的液泡依赖性降解中发挥重要作用。在 tau 病小鼠模型中过表达 BAG3 可降低病理性 tau 水平并减轻突触丢失。BAG3 相互作用蛋白的高通量筛选已经确定了液泡系统中的关键因子；这些包括网格蛋白和小 GTPase 调节剂。这些发现表明 BAG3 是内吞途径的重要调节剂。在这篇评论中，我们讨论了 BAG3 调节液泡系统和 tau 蛋白平衡的潜在机制。
