Madhavan Sidharth S, Roa Diaz Stephanie, Peralta Sawyer, Nomura Mitsunori, King Christina D, Ceyhan Kaya E, Lin Anwen, Bhaumik Dipa, Foulger Anna C, Shah Samah, Blade Thanh, Gray Wyatt, Chamoli Manish, Eap Brenda, Panda Oishika, Diaz Diego, Garcia Thelma Y, Stubbs Brianna J, Ulrich Scott M, Lithgow Gordon J, Schilling Birgit, Verdin Eric, Chaudhuri Asish R, Newman John C
Buck Institute for Research on Aging, Novato, CA 94945, USA; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Division of Geriatrics, University of California, San Francisco, San Francisco, CA 94118, USA.
Buck Institute for Research on Aging, Novato, CA 94945, USA; Division of Geriatrics, University of California, San Francisco, San Francisco, CA 94118, USA.
Cell Chem Biol. 2025 Jan 16;32(1):174-191.e8. doi: 10.1016/j.chembiol.2024.11.001. Epub 2024 Dec 2.
Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.
蛋白质稳态的丧失是衰老和阿尔茨海默病（AD）的一个标志。我们确定β-羟基丁酸酯（βHB），一种酮体，为蛋白质溶解度的调节剂。βHB主要在葡萄糖可用性降低期间提供ATP底物，并通过蛋白质相互作用调节其他细胞过程。我们证明，βHB诱导的蛋白质不溶性不依赖于共价蛋白质修饰、pH值或溶质负荷，并且在给予酮酯后在体内小鼠大脑中可以观察到。这种机制对淀粉样β蛋白等病理性蛋白质具有选择性，外源性βHB可改善淀粉样β蛋白聚集毒性线虫模型中的病理状况。我们使用质谱蛋白质组学生成了βHB诱导的蛋白质不溶性组库，并确定了常见的蛋白质结构域和上游调节因子。我们展示了βHB靶标中神经退行性疾病相关蛋白质的富集以及这些靶标从小鼠大脑中的清除。这些数据表明了一种与衰老和AD相关的蛋白质稳态的代谢调节机制。
