Yang Song-Yu, He Xue-Ying, Isaacs Charles, Dobkin Carl, Miller David, Philipp Manfred
Department of Developmental Biochemistry, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA; Neuroscience Doctoral Program, Graduate Center of the City University of New York, 365 Fifth Avenue, NY 10016, USA.
Department of Developmental Biochemistry, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
J Steroid Biochem Mol Biol. 2014 Sep;143:460-72. doi: 10.1016/j.jsbmb.2014.07.001. Epub 2014 Jul 5.
17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10) is encoded by the HSD17B10 gene mapping at Xp11.2. This homotetrameric mitochondrial multifunctional enzyme catalyzes the oxidation of neuroactive steroids and the degradation of isoleucine. This enzyme is capable of binding to other peptides, such as estrogen receptor α, amyloid-β, and tRNA methyltransferase 10C. Missense mutations of the HSD17B10 gene result in 17β-HSD10 deficiency, an infantile neurodegeneration characterized by progressive psychomotor regression and alteration of mitochondria morphology. 17β-HSD10 exhibits only a negligible alcohol dehydrogenase activity, and is not localized in the endoplasmic reticulum or plasma membrane. Its alternate name - Aβ binding alcohol dehydrogenase (ABAD) - is a misnomer predicated on the mistaken belief that this enzyme is an alcohol dehydrogenase. Misconceptions about the localization and function of 17β-HSD10 abound. 17β-HSD10's proven location and function must be accurately identified to properly assess this enzyme's important role in brain metabolism, especially the metabolism of allopregnanolone. The brains of individuals with Alzheimer's disease (AD) and of animals in an AD mouse model exhibit abnormally elevated levels of 17β-HSD10. Abnormal expression, as well as mutations of the HSD17B10 gene leads to impairment of the structure, function, and dynamics of mitochondria. This may underlie the pathogenesis of the synaptic and neuronal deficiency exhibited in 17β-HSD10 related diseases, including 17β-HSD10 deficiency and AD. Restoration of steroid homeostasis could be achieved by the supplementation of neuroactive steroids with a proper dosing and treatment regimen or by the adjustment of 17β-HSD10 activity to protect neurons. The discovery of this enzyme's true function has opened a new therapeutic avenue for treating AD.
17β-羟类固醇脱氢酶10型（17β-HSD10）由定位于Xp11.2的HSD17B10基因编码。这种同源四聚体线粒体多功能酶催化神经活性类固醇的氧化和异亮氨酸的降解。该酶能够与其他肽结合，如雌激素受体α、淀粉样β蛋白和tRNA甲基转移酶10C。HSD17B10基因的错义突变导致17β-HSD10缺乏症，这是一种婴儿期神经退行性疾病，其特征为进行性精神运动发育迟缓以及线粒体形态改变。17β-HSD10仅表现出可忽略不计的乙醇脱氢酶活性，且并不定位于内质网或质膜。它的别名——Aβ结合乙醇脱氢酶（ABAD）——是一个误称，基于该酶是乙醇脱氢酶这一错误认知。关于17β-HSD10的定位和功能存在诸多误解。必须准确识别17β-HSD10已被证实的定位和功能，以便正确评估该酶在脑代谢尤其是别孕烯醇酮代谢中的重要作用。阿尔茨海默病（AD）患者及AD小鼠模型动物的大脑中17β-HSD10水平异常升高。HSD17B10基因的异常表达以及突变会导致线粒体结构、功能和动力学受损。这可能是17β-HSD10相关疾病（包括17β-HSD10缺乏症和AD）中出现的突触和神经元缺陷发病机制的基础。通过适当给药和治疗方案补充神经活性类固醇或调节17β-HSD10活性以保护神经元，可实现类固醇稳态的恢复。该酶真实功能的发现为治疗AD开辟了一条新的治疗途径。
