Involvement of Type 10 17ß-Hydroxysteroid Dehydrogenase in the Pathogenesis of Infantile Neurodegeneration and Alzheimer's Disease.

Type 10 17ß-hydroxysteroid dehydrogenase (17ß-HSD10) is the HSD17B10 gene product playing an appreciable role in cognitive functions. It is the main hub of exercise-upregulated mitochondrial proteins and is involved in a variety of metabolic pathways including neurosteroid metabolism to regulate allopregnanolone homeostasis. Deacetylation of 17ß-HSD10 by sirtuins helps regulate its catalytic activities. 17ß-HSD10 may also play a critical role in the control of mitochondrial structure, morphology and dynamics by acting as a member of the Parkin/PINK1 pathway, and by binding to cyclophilin D to open mitochondrial permeability pore. 17ß-HSD10 also serves as a component of RNase P necessary for mitochondrial tRNA maturation. This dehydrogenase can bind with the Aß peptide thereby enhancing neurotoxicity to brain cells. Even in the absence of Aß, its quantitative and qualitative variations can result in neurodegeneration. Since elevated levels of 17ß-HSD10 were found in brain cells of Alzheimer's disease (AD) patients and mouse AD models, it is considered to be a key factor in AD pathogenesis. Since data underlying Aß-binding-alcohol dehydrogenase (ABAD) were not secured from reported experiments, ABAD appears to be a fabricated alternative term for the HSD17B10 gene product. Results of this study would encourage researchers to solve the question why elevated levels of 17ß-HSD10 are present in brains of AD patients and mouse AD models. Searching specific inhibitors of 17ß-HSD10 may find candidates to reduce senile neurodegeneration and open new approaches for the treatment of AD.

Fast degradation of atrazine by nZVI-Cu0/PMS: Re-evaluation and quantification of reactive species, generation pathways, and application feasibility.

Additive metal to zero-valent iron (ZVI) could enhance the reduction ability and the additive Cu0 was incorporated to ZVI to accelerate PMS activation with atrazine (ATZ) as target compound. The efficiencies of ATZ degradation and PMS decomposition climbed up firstly and then declined as Cu0 loading increased from 0.01 to 1.00 wt% with the maximums at 0.10 wt%. SO4•-, HO•, Fe(IV), O2•- and 1O2 were generated by nZVI-Cu0/PMS based on the results of electron paramagnetic resonance (EPR) and simultaneous degradation of nitrobenzene, ATZ, and methyl phenyl sulfoxide (PMSO). The rate constant of Fe(IV) and ATZ was estimated as 7 × 104 M-1∙s-1 via the variation of methyl phenyl sulfone (PMSO2)formation at different ATZ concentrations. However, Fe(IV) contributed negligibly to ATZ degradation due to the strong scavenging of Fe(IV) by PMS. SO4•- and HO• were the reactive species responsible for ATZ degradation and the yield ratio of SO4•- and HO• was about 8.70 at initial stage. Preliminary thermodynamic calculation on the possible activation ways revealed that the dominant production of SO4•- might originate from the atomic H reduction of PMS in the surface layer of nZVI-Cu0. Ten products of ATZ degradation were identified by HPLC/ESI/QTOF and the possible degradation pathways were analyzed combined with theoretical calculation on ATZ structure. The decrease of temperature or increase of solution pH led to the decline of ATZ degradation, as well as the individual addition of common ions (HCO3-, Cl-, SO42-, NH4+, NO3- and F-) and natural organic matters (NOM). In real water, ATZ was still efficiently degraded with the decontamination efficiency decreasing in the sequence of tap water > surface water > simulated wastewater > groundwater. For the treatment of ATZ-polluted continuous flow, nZVI-Cu0 in double-layer layout had a higher capacity than the single-layer mode. Meanwhile, the leaching TFe and TCu were limited. The results indicate nZVI-Cu0/PMS is applicable and the multiple-layer layout of nZVI-Cu0 is suggested for ATZ-polluted ground water and soil remediation.

Infantile Neurodegeneration Results from Mutants of 17ß-Hydroxysteroid Dehydrogenase Type 10 Rather Than Aß-Binding Alcohol Dehydrogenase.

Type 10 17ß-hydroxysteroid dehydrogenase (17ß-HSD10), a homo-tetrameric multifunctional protein with 1044 residues encoded by the HSD17B10 gene, is necessary for brain cognitive function. Missense mutations result in infantile neurodegeneration, an inborn error in isoleucine metabolism. A 5-methylcytosine hotspot underlying a 388-T transition leads to the HSD10 (p.R130C) mutant to be responsible for approximately half of all cases suffering with this mitochondrial disease. Fewer females suffer with this disease due to X-inactivation. The binding capability of this dehydrogenase to Aß-peptide may play a role in Alzheimer's disease, but it appears unrelated to infantile neurodegeneration. Research on this enzyme was complicated by reports of a purported Aß-peptide-binding alcohol dehydrogenase (ABAD), formerly referred to as endoplasmic-reticulum-associated Aß-binding protein (ERAB). Reports concerning both ABAD and ERAB in the literature reflect features inconsistent with the known functions of 17ß-HSD10. It is clarified here that ERAB is reportedly a longer subunit of 17ß-HSD10 (262 residues). 17ß-HSD10 exhibits L-3-hydroxyacyl-CoA dehydrogenase activity and is thus also referred to in the literature as short-chain 3-hydorxyacyl-CoA dehydrogenase or type II 3-hydorxyacyl-CoA dehydrogenase. However, 17ß-HSD10 is not involved in ketone body metabolism, as reported in the literature for ABAD. Reports in the literature referring to ABAD (i.e., 17ß-HSD10) as a generalized alcohol dehydrogenase, relying on data underlying ABAD's activities, were found to be unreproducible. Furthermore, the rediscovery of ABAD/ERAB's mitochondrial localization did not cite any published research on 17ß-HSD10. Clarification of the purported ABAD/ERAB function derived from these reports on ABAD/ERAB may invigorate this research field and encourage new approaches to the understanding and treatment of HSD17B10-gene-related disorders. We establish here that infantile neurodegeneration is caused by mutants of 17ß-HSD10 but not ABAD, and so we conclude that ABAD represents a misnomer employed in high-impact journals.

3-Hydroxyacyl-CoA and Alcohol Dehydrogenase Activities of Mitochondrial Type 10 17ß-Hydroxysteroid Dehydrogenase in Neurodegeneration Study.

BACKGROUND: Mitochondrial 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) is necessary for brain cognitive function, but its studies were confounded by reports of Aß-peptide binding alcohol dehydrogenase (ABAD), formerly endoplasmic reticulum-associated Aß-peptide binding protein (ERAB), for two decades so long as ABAD serves as the alternative term of 17ß-HSD10. OBJECTIVE: To determine whether those ABAD reports are true or false, even if they were published in prestigious journals. METHODS: 6xHis-tagged 17ß-HSD10 was prepared and characterized by well-established experimental procedures. RESULTS: The N-terminal 6xHis tag did not significantly interfere with the dehydrogenase activities of 17ß-HSD10, but the kinetic constants of its 3-hydroxyacyl-CoA dehydrogenase activity are drastically distinct from those of ABAD, and it was not involved in ketone body metabolism as previously reported for ABAD. Furthermore, it was impossible to measure its generalized alcohol dehydrogenase activities underlying the concept of ABAD because the experimental procedures described in ABAD reports violated basic chemical and/or biochemical principles. More incredibly, both authors and journals had not yet agreed to make any corrigenda of ABAD reports. CONCLUSION: Brain 17ß-HSD10 plays a key role in neurosteroid metabolism and further studies in this area may lead to potential treatments of neurodegeneration including AD.

17ß-Hydroxysteroid dehydrogenases and neurosteroid metabolism in the central nervous system.

17ß-Hydroxysteroid dehydrogenases are indispensable for downstream enzyme steps of the neurosteroidogenesis. Neurosteroids are synthesized de novo in neurons and glia from cholesterol transported into mitochondria, or by conversion from proneurosteroids, e. g. dehydroepiandrosterone (DHEA) and pregnenolone, through the same metabolic pathway as revealed in the de novo neurosteroidogenesis. Hormonal steroids generated from endocrine glands are transported into brain from the circulation to exert neuronal activity via genomic pathway, whereas neurosteroids produced in brain cells without genomic targets identified could bind to cell surface targets, e.g., GABAA or NMDA receptors and elicit antidepressant, anxiolytic, anticonvulsant and anesthetic effects by regulating neuroexcitability. In a broad sense, neurosteroids include hormonal steroids in brain, and they are irrespective of origin playing important roles in brain development including neuroprotection, neurogenesis and neural plasticity. They are also a critical element in cognitive and memory functions. Mitochondrial 17ß-HSD10, encoded by the HSD17B10 gene mapping to Xp11.2, is found in various brain regions, essential for the maintenance of neurosteroid homeostasis. Mutations identified in this gene resulted in two distinct brain diseases, namely HSD10 deficiency and MRXS10, of which clinical presentations and pathogenetic mechanisms are quite different. Since elevated levels of 17ß-HSD10 was found in brains of Alzheimer's disease patients and AD mouse model, it may also act as an adverse factor in the AD pathogenesis due to an imbalance of neurosteroid metabolism.

Roles of Mitochondrial 17ß-Hydroxysteroid Dehydrogenase Type 10 in Alzheimer's Disease.

17ß-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17ß-HSD10, is overexpressed in brain cells of Alzheimer's disease (AD) patients. It was reported to be involved in AD pathogenesis as the endoplasmic reticulum-associated amyloid-ß binding protein (ERAB) and as amyloid-ß binding alcohol dehydrogenase (ABAD). However, the exaggerated catalytic efficiencies for ERAB/ABAD in these reports necessitated the re-characterization of the catalytic functions of this brain enzyme. In addition to isoleucine metabolism, 17ß-HSD10 is also responsible for the mitochondrial metabolism of neurosteroids such as 5α-androstane-3α,17ß-diol and 17ß-estradiol. These neurosteroids are inactivated by the oxidation catalyzed by 17ß-HSD10. Since neurosteroid homeostasis is presumably essential for cognitive function, analysis of the impact of 17ß-HSD10 and its inhibitor, amyloid-ß peptide (Aß), on the metabolism of neuroactive steroids offers a new approach to AD pathogenesis.

Photosynthetic and growth responses of Schima superba seedlings to sulfuric and nitric acid depositions.

A continuing rise in acid deposition can cause forest degradation. In China, acid deposition has converted gradually from sulfuric acid deposition (SAD) to nitric acid deposition (NAD). However, the differing responses of photosynthesis and growth to depositions of sulfuric vs. nitric acid have not been well studied. In this study, 1-year-old seedlings of Schima superba, a dominant species in subtropical forests, were treated with two types of acid deposition SO4 (2-)/NO3 (-) ratios (8:1 and 0.7:1) with two applications (foliar spraying and soil drenching) at two pH levels (pH 3.5 and pH 2.5) over a period of 18 months. The results showed that the intensity, acid deposition type, and spraying method had significant effects on the physiological characteristics and growth performance of seedlings. Acid deposition at pH 2.5 via foliar application reduced photosynthesis and growth of S. superba, especially in the first year. Unlike SAD, NAD with high acidity potentially alleviated the negative effects of acidity on physiological properties and growth, probably due to a fertilization effect that improved foliar nitrogen and chlorophyll contents. Our results suggest that trees were damaged mainly by direct acid stress in the short term, whereas in the long term, soil acidification was also likely to be a major risk to forest ecosystems. Our data suggest that the shift in acid deposition type may complicate the ongoing challenge of anthropogenic acid deposition to ecosystem stability.

Roles of 17ß-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders.

17ß-Hydroxysteroid dehydrogenase type 10 (17ß-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-ß, and tRNA methyltransferase 10C. Missense mutations of the HSD17B10 gene result in 17ß-HSD10 deficiency, an infantile neurodegeneration characterized by progressive psychomotor regression and alteration of mitochondria morphology. 17ß-HSD10 exhibits only a negligible alcohol dehydrogenase activity, and is not localized in the endoplasmic reticulum or plasma membrane. Its alternate name - Aß 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 17ß-HSD10 abound. 17ß-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 17ß-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 17ß-HSD10 related diseases, including 17ß-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 17ß-HSD10 activity to protect neurons. The discovery of this enzyme's true function has opened a new therapeutic avenue for treating AD.

Transcription start sites and epigenetic analysis of the HSD17B10 proximal promoter.

BACKGROUND: Hydroxysteroid (17beta) dehydrogenase X (HSD10) is a multifunctional protein encoded by the HSD17B10 gene at Xp11.2. In response to stress or hypoxia-ischemia its levels increase rapidly. Expression of this gene is also elevated significantly in colonic mucosa of the inactive ulcerative colitis patients. However, accurate information about its several transcripts is still lacking, and additional evidence for its escape from X-chromosome inactivation remains to be obtained in order to help settle a debate (He XY, Dobkin C, Yang SY: Does the HSD17B10 gene escape from X-inactivation? Eur J Hum Genet 2011, 19: 123-124). RESULTS: Two major HSD17B10 transcription start sites were identified by primer extension at -37 and -6 as well as a minor start site at -12 nucleotides from the initiation codon ATG. Epigenetic analysis of the 5'-flanking region of the HSD17B10 gene showed that there was little 5-methylcytosine (< 3%) in a normal male, and that none of CpG dinucleotides in the CpG island approached 50% methylation in females. CONCLUSION: The actual length of first exon of the HSD17B10 gene was found to be about a quarter larger than that originally reported. Its transcripts result from a slippery transcription complex. The hypomethylation of the CpG island provides additional evidence for the variable escape of the HSD17B10 gene from X-chromosome inactivation which could influence the range of severity of HSD10 deficiency, an inherited error in isoleucine metabolism, in heterozygous females.

A 5-methylcytosine hotspot responsible for the prevalent HSD17B10 mutation.

Approximately half of the cases of hydroxysteroid (17ß) dehydrogenase X (HSD10) deficiency are due to a missense C>T mutation in exon 4 of the HSD17B10 gene. The resulting HSD10 (p.R130C) loses most or all catalytic functions, and the males with this mutation have a much more severe clinical phenotype than those carrying p.V65A, p.L122V, or p.E249Q mutations. We found that the mutated cytosine which is +2259 nucleotide from the ATG of the gene, is >90% methylated in both the active and inactive X chromosomes in two normal females as well as in the X chromosome of a normal male. Since 5-methylcytosine is prone to conversion to thymine by deamination, the methylation of this cytosine in normal X chromosomes provides an explanation for the prevalence of the p.R130C mutation among patients with HSD10 deficiency. The substitution of arginine for cysteine eliminates several hydrogen bonds and reduces the van der Waals interaction between HSD10 subunits. The resulting disruption of protein structure impairs some if not all of the catalytic and non-enzymatic functions of HSD10. A meta-analysis of residual HSD10 activity in eight patients with the p.R130C mutation showed an average 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) activity of only 6 (±5) % of the normal control level. This is significantly lower than in cells of patients with other, clinically milder mutations and suggests that the loss of HSD10/MHBD activity is a marker for the disorder.

A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability.

Hydroxysteroid (17beta) dehydrogenase 10 (HSD10) is a mitochondrial multifunctional enzyme encoded by the HSD17B10 gene. Missense mutations in this gene result in HSD10 deficiency, whereas a silent mutation results in mental retardation, X-linked, syndromic 10 (MRXS10). Here we report a novel missense mutation found in the HSD17B10 gene, namely c.194T>C transition (rs104886492), brought about by the loss of two forked methyl groups of valine 65 in the HSD10 active site. The affected boy, who possesses mutant HSD10 (p.V65A), has a neurological syndrome with metabolic derangements, choreoathetosis, refractory epilepsy and learning disability. He has no history of acute decompensation or metabolic acidosis whereas his urine organic acid profile, showing elevated levels of 2-methyl-3-hydroxybutyrate and tiglylglycine, is characteristic of HSD10 deficiency. His HSD10 activity was much lower than the normal control level, with normal ß-ketothiolase activity. The c.194T>C mutation in HSD17B10 can be identified by the restriction fragment polymorphism analysis, thereby facilitating the screening of this novel mutation in individuals with intellectual disability of unknown etiology and their family members much easier. The patient's mother is an asymptomatic carrier, and has a mixed ancestry (Hawaiian, Japanese and Chinese). This demonstrates that HSD10 deficiency patients are not confined to a particular ethnicity although previously reported cases were either Spanish or German descendants.

Hydroxysteroid (17ß) dehydrogenase X in human health and disease.

Hydroxysteroid (17ß) dehydrogenase 10 (HSD10), the HSD17B10 gene product, is a mitochondrial NAD(+)-dependent dehydrogenase. There are two outstanding features of this vital enzyme: (a) the versatility of its catalytic endowment is attributed to the flexibility of its active site to accommodate diverse substrates such as steroids, fatty acids, bile acid, and xenobiotics; (b) its capacity to bind other proteins and peptides. For example, it tightly binds with three identical subunits to compose a homotetramer. The homotetramer then binds with two other proteins, namely, RNA (guanine-9-)methyl-transferase domain containing-1 and KIAA0391, to form mitochondrial RNase P. Furthermore, various HSD10 functions are inhibited when the enzyme is bound by amyloid-ß peptide or estrogen receptor alpha. Missense mutations of HSD10 may cause neurodegeneration related to HSD10 deficiency, whereas a silent mutation of HSD10 results in mental retardation, choreoathetosis and abnormal behavior (MRXS10). The clinical condition of some HSD10 patients mimics mitochondrial disorders. Since normal HSD10 function is essential for brain cognitive activity, elevated levels of HSD10 found in brains of Alzheimer disease (AD) patients and mouse AD model might counterbalance the inhibition of HSD10 by amyloid-ß peptide. The investigation of HSD10 may lead to a better understanding of AD pathogenesis.

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

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 (17beta) 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 approximately 1.3. HSD10(E249Q) was unable to catalyze the dehydrogenation of 2-methyl-3-hydroxybutyryl-CoA and the oxidation of allopregnanolone, a positive modulator of the gamma-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 (17beta) dehydrogenase 10 deficiency.

HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids.

The HSD17B10 gene maps on chromosome Xp11.2, a region highly associated with X-linked mental retardation. This gene encodes HSD10, a mitochondrial multifunctional enzyme that plays a significant part in the metabolism of neuroactive steroids and the degradation of isoleucine. The HSD17B10 gene is composed of six exons and five introns. Its exon 5 is an alternative exon such that there are several HSD17B10 mRNA isoforms in brain. A silent mutation (c.605C-->A) and three missense mutations (c.395C-->G; c.419C-->T; c.771A-->G), respectively, cause the X-linked mental retardation, choreoathetosis, and abnormal behavior (MRXS10) and the hydroxyacyl-CoA dehydrogenase II deficiency. The latter condition seems to be a multifactorial disease due to the disturbance of more than one metabolic pathway by the HSD10 deficiency. HSD10 inactivates the positive modulators of GABAA receptors, and plays a role in the maintenance of GABAergic neuronal function. This working model may account for the mental retardation of these patients. The dehydrogenase activity is slightly inhibited by the binding of amyloid-beta peptide to the loop D of HSD10. Elevated levels of HSD10 were observed in hippocampi of Alzheimer disease patients so this multifunctional enzyme may be related to Alzheimer disease pathogenesis; however, the molecular mechanism of its involvement remains to be ascertained.

3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease.

3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. HAD has a preference for medium chain substrates, whereas short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) acts on a wide spectrum of substrates, including steroids, cholic acids, and fatty acids, with a preference for short chain methyl-branched acyl-CoAs. Therefore, HAD should not be referred to as SCHAD. SCHAD is not a member of the HAD family, but instead, belongs to the short chain dehydrogenase/reductase superfamily. Previously reported cases of SCHAD deficiency are due to an inherited HAD deficiency. SCHAD, also known as 17beta-hydroxysteroid dehydrogenase type 10, is important in brain development and aging. Abnormal levels of SCHAD in certain brain regions may contribute to the pathogenesis of some neural disorders. The human SCHAD gene and its protein product, SCHAD, are potential targets for intervention in conditions, such as Alzheimer's disease, Parkinson's disease, and an X-linked mental retardation, that may arise from the impaired degradation of branched chain fatty acid and isoleucine.