He Xue-Ying, Frackowiak Janusz, Yang Song-Yu
Department of Molecular Biology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
J Pers Med. 2025 Aug 1;15(8):346. doi: 10.3390/jpm15080346.
Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) is the gene product. It plays an appreciable part in the carcinogenesis and pathogenesis of neurodegeneration, such as Alzheimer's disease and infantile neurodegeneration. This mitochondrial, homo-tetrameric protein is a central hub in various metabolic pathways, e.g., branched-chain amino acid degradation and neurosteroid metabolism. It can bind to other proteins carrying out diverse physiological functions, e.g., tRNA maturation. It has also previously been proposed to be an Aβ-binding alcohol dehydrogenase (ABAD) or endoplasmic reticulum-associated Aβ-binding protein (ERAB), although those reports are controversial due to data analyses. For example, the reported value of some substrate of ABAD/ERAB was five times higher than its natural solubility in the assay employed to measure . Regarding any reported " competitive inhibition" of ABAD/ERAB by Aβ, the value estimations were likely impacted by non-physiological concentrations of 2-octanol at high concentrations of vehicle DMSO and, therefore, are likely artefactual. Certain data associated with ABAD/ERAB were found not reproducible, and multiple experimental approaches were undertaken under non-physiological conditions. In contrast, 17β-HSD10 studies prompted a conclusion that Aβ inhibited 17β-HSD10 activity, thus harming brain cells, replacing a prior supposition that "ABAD" mediates Aβ neurotoxicity. Furthermore, it is critical to find answers to the question as to why elevated levels of 17β-HSD10, in addition to Aβ and phosphorylated Tau, are present in the brains of AD patients and mouse AD models. Addressing this question will likely prompt better approaches to develop treatments for Alzheimer's disease.
10型17β-羟基类固醇脱氢酶（17β-HSD10）是该基因的产物。它在神经退行性疾病（如阿尔茨海默病和婴儿神经退行性疾病）的致癌作用和发病机制中起着重要作用。这种线粒体同四聚体蛋白是各种代谢途径的核心枢纽，例如支链氨基酸降解和神经甾体代谢。它可以与执行多种生理功能的其他蛋白质结合，例如tRNA成熟。此前也有人提出它是一种β淀粉样蛋白结合醇脱氢酶（ABAD）或内质网相关β淀粉样蛋白结合蛋白（ERAB），尽管由于数据分析这些报道存在争议。例如，在用于测量的实验中，报道的某些ABAD/ERAB底物的值比其天然溶解度高五倍。关于任何报道的β淀粉样蛋白对ABAD/ERAB的“竞争性抑制”，在高浓度载体二甲基亚砜存在下，2-辛醇的非生理浓度可能影响了值的估计，因此可能是人为造成的。发现与ABAD/ERAB相关的某些数据不可重复，并且在非生理条件下采用了多种实验方法。相比之下，17β-HSD10的研究得出结论，β淀粉样蛋白抑制17β-HSD10活性，从而损害脑细胞，取代了先前“ABAD”介导β淀粉样蛋白神经毒性的假设。此外，至关重要的是要找到答案，即为什么除了β淀粉样蛋白和磷酸化 Tau 之外 AD 患者和小鼠 AD 模型的大脑中还存在升高水平的17β-HSD10。解决这个问题可能会促使开发更好的阿尔茨海默病治疗方法。
