Harnessing Functional Plasticity of Enzymes:  A Fluorogenic Probe for Imaging 17β-HSD10 Dehydrogenase, an Enzyme Involved in Alzheimer's and Parkinson's Diseases

Froemming, Mary K.; Sameš, Dalibor

doi:10.1021/ja072601x

Cited by 45 publications

(29 citation statements)

References 18 publications

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“…ABAD is identical to SCHAD (human brain short chain l-3-hydroxyacetyl-CoA dehydrogenase type II, E.C.1.1.1.35), which is encoded by the gene HADH II (also called HSD10, 17b-hydroxysteroid dehydrogenase). [68,69] The ABAD-Ab complex has been detected in the brains of AD patients and localized to mitochondria. [70] ABAD is upregulated in AD brains (hippocampus) and is also present in activated astrocytes in the amyloid plaque corona.…”

Section: Induction and Impairment Of Autophagymentioning

confidence: 99%

Alzheimer's Disease: From Pathology to Therapeutic Approaches

2009

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Mind how you go: The current strategies for the development of therapies for Alzheimer's disease are very diverse. Particular attention is given to the search for inhibitors (see picture for two examples) of the proteolytic enzyme beta- and gamma-secretase, which inhibits the cleavage of the amyloid precursor proteins into amyloid beta peptides, from which the disease-defining deposits of plaque in the brains of Alzheimer's patients originates.Research on senile dementia and Alzheimer's disease covers an extremely broad range of scientific activities. At the recent international meeting of the Alzheimer's Association (ICAD 2008, Chicago) more than 2200 individual scientific contributions were presented. The aim of this Review is to give an overview of the field and to outline its main areas, starting from behavioral abnormalities and visible pathological findings and then focusing on the molecular details of the pathology. The "amyloid hypothesis" of Alzheimer's disease is given particular attention, since the majority of the ongoing therapeutic approaches are based on its theoretical framework.

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Section: Induction and Impairment Of Autophagymentioning

confidence: 99%

Alzheimer's Disease: From Pathology to Therapeutic Approaches

2009

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“…CHANA is a nonfluorescent substrate under assay conditions, whereas the reaction product, CHANK (cyclohexenyl amine naphthalene ketone) fluoresces in non-aqueous environments, e.g. in cell membranes [56]. Due to these different photochemical properties, the selective detection of the accumulation of CHANK is possible.…”

Section: Therapeutic Targets and Development Of Assaysmentioning

confidence: 99%

Mitochondrial β-amyloid in Alzheimer's disease

Borger

Aitken

Muirhead

et al. 2011

Biochemical Society Transactions

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It is well established that the intracellular accumulation of Aβ (amyloid β-peptide) is associated with AD (Alzheimer's disease) and that this accumulation is toxic to neurons. The precise mechanism by which this toxicity occurs is not well understood; however, identifying the causes of this toxicity is an essential step towards developing treatments for AD. One intracellular location where the accumulation of Aβ can have a major effect is within mitochondria, where mitochondrial proteins have been identified that act as binding sites for Aβ, and when binding occurs, a toxic response results. At one of these identified sites, an enzyme known as ABAD (amyloid-binding alcohol dehydrogenase), we have identified changes in gene expression in the brain cortex, following Aβ accumulation within mitochondria. Specifically, we have identified two proteins that are up-regulated not only in the brains of transgenic animal models of AD but also in those of human sufferers. The increased expression of these proteins demonstrates the complex and counteracting pathways that are activated in AD. Previous studies have identified approximate contact sites between ABAD and Aβ; on basis of these observations, we have shown that by using a modified peptide approach it is possible to reverse the expression of these two proteins in living transgenic animals and also to recover mitochondrial and behavioural deficits. This indicates that the ABAD-Aβ interaction is potentially an interesting target for therapeutic intervention. To explore this further we used a fluorescing substrate mimic to measure the activity of ABAD within living cells, and in addition we have identified chemical fragments that bind to ABAD, using a thermal shift assay.

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“…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%

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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Harnessing Functional Plasticity of Enzymes: A Fluorogenic Probe for Imaging 17β-HSD10 Dehydrogenase, an Enzyme Involved in Alzheimer's and Parkinson's Diseases

Cited by 45 publications

References 18 publications

Alzheimer's Disease: From Pathology to Therapeutic Approaches

Alzheimer's Disease: From Pathology to Therapeutic Approaches

Mitochondrial β-amyloid in Alzheimer's disease

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

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