Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Institute for Aging Studies of the Department of Medicine of the Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Nat Commun. 2022 Jul 21;13(1):4220. doi: 10.1038/s41467-022-31869-1.
Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration.
伴侣介导的自噬活性对于细胞对抗蛋白毒性至关重要，随着年龄的增长而下降，在实验性遗传模型中预防这种下降已被证明是有益的。在这里，我们已经确定了我们小组之前开发的选择性伴侣介导的自噬激活剂的作用机制，并利用这些信息生成具有良好脑暴露的口服生物利用的伴侣介导的自噬激活剂。伴侣介导的自噬激活分子稳定了维甲酸受体α（已知的伴侣介导的自噬内源性抑制剂）与其共阻遏物核受体共抑制因子 1 之间的相互作用，导致维甲酸受体α转录程序的离散子集发生变化，从而导致选择性伴侣介导的自噬激活。伴侣介导的自噬激活分子在体内激活该途径，并改善色素性视网膜炎小鼠模型中的视网膜变性。我们的发现揭示了一种针对伴侣介导的自噬激活的药理学靶向机制，并为视网膜变性提出了一种治疗策略。
