Multiple functions of type 10 17β-hydroxysteroid dehydrogenase

Yang, Song‐Yu; He, Xue‐Ying; Schulz, Horst

doi:10.1016/j.tem.2005.03.006

Cited by 113 publications

(101 citation statements)

References 61 publications

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“…As both non-Tg and 3xTgAD mice were treated with the same dose of APα under exactly the same conditions, the decrease in APα level must be attributable to either decreased absorption or increased metabolism. Our working hypothesis is that the decrease in APα is due to metabolism via increased expression of 17β-hydroxysteroid dehydrogenase (17βHSD, aka ERAB and ABAD) (4,29,30). This enzyme is significantly elevated in APP transgenic AD mice but not in normal controls (29,31).…”

Section: Discussionmentioning

confidence: 99%

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Wang

Singh²,

Liu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

236

266

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Our previous analyses showed that allopregnanolone (APα) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APα to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between APα-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells. Learning and memory function was assessed using the hippocampal-dependent trace eye-blink conditioning paradigm. At 3 months, basal level of BrdU+ cells in the SGZ of 3xTgAD mice was significantly lower relative to non-Tg mice, despite the lack of evident AD pathology. APα significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude. As with the deficit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. APα reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APα-induced survival of neural progenitors was significantly correlated with APα-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Aβ, may contribute to the cognitive phenotype of AD, and that APα could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Wang

Singh²,

Liu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

236

266

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“…ss#HSD10 -0005 95210060). 1 To whom correspondence should be addressed. E-mail: syang@mail.csi.cuny.edu.…”

Section: Resultsmentioning

confidence: 99%

“…Its etiopathology was generally attributed to a defect of isoleucine metabolism (9, 27-31). However, MHBD or 3-hydroxyacyl-CoA dehydrogenase 2 (Hadh2) (10, 32) only represents one of the multiple functions of HSD10 (1,8). To clarify confusions of the multiplicity of names for the gene and gene product, the Human Genome Organization (HUGO) recently announced that HSD17B10 gene and hydroxysteroid (17␤) dehydrogenase 10 replaced HADH2 gene and hydroxyacyl-CoA dehydrogenase II as the official gene symbol and the designation of gene product, respectively (10,32).…”

Section: Discussionmentioning

confidence: 99%

“…H ydroxysteroid (17␤) dehydrogenase 10 (HSD10) is a mitochondrial multifunctional enzyme (1,2), which catalyzes the oxidation of steroid modulators of ␥-aminobutyric acid type A (GABA A ) receptors (3), steroid hormones (4,5), and xenobiotics (6). It also exhibits short-chain 3-hydroxy-2-methylacylCoA dehydrogenase activity such that it is essential for the degradation of isoleucine (7)(8)(9).…”

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confidence: 99%

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Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism

Yang¹,

He²,

Olpin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the HSD17B10 gene were identified in two previously described mentally retarded males. A point mutation c.776G>C was found from a survivor (SV), whereas a potent mutation, c.419C>T, was identified in another deceased case (SF) with undetectable hydroxysteroid (17␤) dehydrogenase 10 (HSD10) activity. Protein levels of mutant HSD10(R130C) in patient SF and HSD10(E249Q) in patient SV were about half that of HSD10 in normal controls. The E249Q mutation appears to affect HSD10 subunit interactions, resulting in an allosteric regulatory enzyme. For catalyzing the oxidation of allopregnanolone by NAD ؉ the Hill coefficient of the mutant enzyme is Ϸ1.3. HSD10(E249Q) was unable to catalyze the dehydrogenation of 2-methyl-3-hydroxybutyryl-CoA and the oxidation of allopregnanolone, a positive modulator of the ␥-aminobutyric acid type A receptor, at low substrate concentrations. Neurosteroid homeostasis is critical for normal cognitive development, and there is increasing evidence that a blockade of isoleucine catabolism alone does not commonly cause developmental disabilities. The results support the theory that an imbalance in neurosteroid metabolism could be a major cause of the neurological handicap associated with hydroxysteroid (17␤) dehydrogenase 10 deficiency.developmental disabilities ͉ HSD10 deficiency ͉ hydroxyacyl-CoA dehydrogenase

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“…Three N. vectensis genes clustered with HSD17B10, including two genes on the same scaffold (Cluster D); this pattern is consistent with diversification in the N. vectensis lineage. 17β-HSD 10 can oxidize steroids (at several positions, including the 17β-OH dehydrogenation of estradiol and 3α-OH dehydrogenation of androgens), bile acids and fatty acids (Shafquat et al, 2003;Yang et al, 2005). In mammals, 17β-HSD 10 also binds β-amyloid proteins and may play a role in neurodegenerative diseases, such as Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

Steroid metabolism in cnidarians: Insights from Nematostella vectensis

Tarrant

Reitzel

Blomquist

et al. 2009

Molecular and Cellular Endocrinology

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Cnidarians occupy a key evolutionary position as a sister group to bilaterian animals. While cnidarians contain a diverse complement of steroids, sterols, and other lipid metabolites, relatively little is known of the endogenous steroid metabolism or function in cnidarian tissues. Incubations of cnidarian tissues with steroid substrates have indicated the presence of steroid metabolizing enzymes, particularly enzymes with 17β-hydroxysteroid dehydrogenase (17β-HSD) activity. Through analysis of the genome of the starlet sea anemone, Nematostella vectensis, we identified a suite of genes in the short chain dehydrogenase/reductase (SDR) superfamily including homologs of genes that metabolize steroids in other animals. A more detailed analysis of Hsd17b4 revealed complex evolutionary relationships, apparent intron loss in several taxa, and predominantly adult expression in N. vectensis. Due to its ease of culture and available molecular tools N. vectensis is an excellent model for investigation of cnidarian steroid metabolism and gene function. KeywordsEvolution, hydroxysteroid dehydrogenase, short chain dehydrogenase/reductase Abbreviations CYP HSD AKR 3

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Multiple functions of type 10 17β-hydroxysteroid dehydrogenase

Cited by 113 publications

References 61 publications

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism

Steroid metabolism in cnidarians: Insights from Nematostella vectensis

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