title: Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders.
abstract: 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.
authors.affiliation: 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. Electronic address: songyu.yang@csi.cuny.edu.
authors.forename: Song-Yu
authors.initials: SY
authors.lastname: Yang
authors.affiliation: Department of Developmental Biochemistry, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
authors.forename: Xue-Ying
authors.initials: XY
authors.lastname: He
authors.affiliation: Department of Developmental Biochemistry, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Isaacs
authors.affiliation: Department of Molecular Genetics, 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.
authors.forename: Carl
authors.initials: C
authors.lastname: Dobkin
authors.affiliation: Department of Molecular Biology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.affiliation: Department of Chemistry, Lehman College of CUNY, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA; Biochemistry Doctoral Program, Graduate Center of the City University of New York, 365 Fifth Avenue, NY 10016, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Philipp
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000473:pathology*
chemical_list: D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase
keywords: ABAD; Alzheimer'; Developmental intellectual disabilities; HSD17B10 gene; Metabolism of allopregnanolone; Mitochondria; Multifunctional protein; Neuroactive steroids; s disease