Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of Excessive Monoamine Oxidase A/B Activity Protects Against Stress-induced Neuronal Death in Huntington Disease.

ABSTRACT: Monoamine oxidases (MAO) are important components of the homeostatic machinery that maintains the levels of monoamine neurotransmitters, including dopamine, in balance. Given the imbalance in dopamine levels observed in Huntington disease (HD), the aim of this study was to examine MAO activity in a mouse striatal cell model of HD and in human neural cells differentiated from control and HD patient-derived induced pluripotent stem cell (hiPSC) lines. We show that mouse striatal neural cells expressing mutant huntingtin (HTT) exhibit increased MAO expression and activity. We demonstrate using luciferase promoter assays that the increased MAO expression reflects enhanced epigenetic activation in striatal neural cells expressing mutant HTT. Using cellular stress paradigms, we further demonstrate that the increase in MAO activity in mutant striatal neural cells is accompanied by enhanced susceptibility to oxidative stress and impaired viability. Treatment of mutant striatal neural cells with MAO inhibitors ameliorated oxidative stress and improved cellular viability. Finally, we demonstrate that human HD neural cells exhibit increased MAO-A and MAO-B expression and activity. Altogether, this study demonstrates abnormal MAO expression and activity and suggests a potential use for MAO inhibitors in HD.

SUBMITTER: Ooi J

PROVIDER: S-EPMC4586002 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

The endoplasmic reticulum stress sensor, ATF6?, protects against neurotoxin-induced dopaminergic neuronal death.

Project description:Oxidative stress and endoplasmic reticulum (ER) stress are thought to contribute to the pathogenesis of various neurodegenerative diseases including Parkinson disease (PD), however, the relationship between these stresses remains unclear. ATF6? is an ER-membrane-bound transcription factor that is activated by protein misfolding in the ER and functions as a critical regulator of ER quality control proteins in mammalian cells. The goal of this study was to explore the cause-effect relationship between oxidative stress and ER stress in the pathogenesis of neurotoxin-induced model of PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopaminergic neurotoxin known to produce oxidative stress, activated ATF6? and increased ER chaperones and ER-associated degradation (ERAD) component in dopaminergic neurons. Importantly, MPTP induced formation of ubiquitin- immunopositive inclusions and loss of dopaminergic neurons more prominently in mice deficient in ATF6? than in wild-type mice. Cultured cell experiments revealed that 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative stress not only promoted phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) but also enhanced interaction between phosphorylated p38MAPK and ATF6?, leading to increment in transcriptional activator activity of ATF6?. Thus, our results revealed a link between oxidative stress and ER stress by showing the importance of ATF6? in the protection of the dopaminergic neurons from MPTP that occurs through oxidative stress-induced activation of ATF6? and p38MAPK-mediated enhancement of ATF6? transcriptional activity.

| S-EPMC3048681 | biostudies-literature

Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia.

Project description:Recent data have shown that TLR4 performs a key role in cerebral ischemia-reperfusion injury which serves as the origin of the immunological inflammatory reactions. However, the therapeutic effects of pharmacological inhibitions of TLR4 and its immediate down-stream pathway remain to be uncovered. In the present study, on mice, intracerebroventricular injection of resatorvid (TLR4 signal inhibitor; 0.01 ?g) significantly reduced infarct volume and improved neurological score after middle cerebral artery occlusion and reperfusion. The levels of phospho-p38, nuclear factor-kappa B, and matrix metalloproteinase 9 expressions were significantly suppressed in the resatorvid-treated group. In addition, NOX4 associates with TLR4 after cerebral ischemia-reperfusion seen in mice and human. Genetic and pharmacological inhibitions of TLR4 each reduced NOX4 expression, leading to suppression of oxidative/nitrative stress and of neuronal apoptosis. These data suggest that resatorvid has potential as a therapeutic agent for stroke since it inhibits TLR4-NOX4 signaling which may be the predominant causal pathway.

| S-EPMC3508453 | biostudies-other

The endoplasmic reticulum stress response factor CHOP-10 protects against hypoxia-induced neuronal death.

Project description:Hypoxia-induced gene expression is a critical determinant of neuron survival after stroke. Understanding the cell autonomous genetic program controlling adaptive and pathological transcription could have important therapeutic implications. To identify the factors that modulate delayed neuronal apoptosis after hypoxic injury, we developed an in vitro culture model that recapitulates these divergent responses and characterized the sequence of gene expression changes using microarrays. Hypoxia induced a disproportionate number of bZIP transcription factors and related targets involved in the endoplasmic reticulum stress response. Although the temporal and spatial aspects of ATF4 expression correlated with neuron loss, our results did not support the anticipated pathological role for delayed CHOP expression. Rather, CHOP deletion enhanced neuronal susceptibility to both hypoxic and thapsigargin-mediated injury and attenuated brain-derived neurotrophic factor-induced neuroprotection. Also, enforced expression of CHOP prior to the onset of hypoxia protected wild-type cultures against subsequent injury. Collectively, these findings indicate CHOP serves a more complex role in the neuronal response to hypoxic stress with involvement in both ischemic preconditioning and delayed neuroprotection.

| S-EPMC2898390 | biostudies-literature

The protective role of Bax inhibitor-1 against chronic mild stress through the inhibition of monoamine oxidase A.

Project description:The anti-apoptotic protein Bax inhibitor-1 (BI-1) is a regulator of apoptosis linked to endoplasmic reticulum (ER) stress. It has been hypothesized that BI-1 protects against neuron degenerative diseases. In this study, BI-1⁻/⁻ mice showed increased vulnerability to chronic mild stress accompanied by alterations in the size and morphology of the hippocampi, enhanced ROS accumulation and an ER stress response compared with BI-1⁺/⁺ mice. BI-1⁻/⁻ mice exposed to chronic mild stress showed significant activation of monoamine oxidase A (MAO-A), but not MAO-B, compared with BI-1⁺/⁺ mice. To examine the involvement of BI-1 in the Ca²⁺-sensitive MAO activity, thapsigargin-induced Ca²⁺ release and MAO activity were analyzed in neuronal cells overexpressing BI-1. The in vitro study showed that BI-1 regulates Ca²⁺ release and related MAO-A activity. This study indicates an endogenous protective role of BI-1 under conditions of chronic mild stress that is primarily mediated through Ca²⁺-associated MAO-A regulation.

| S-EPMC3844965 | biostudies-literature

Inhibition of the AIF/CypA complex protects against intrinsic death pathways induced by oxidative stress.

Project description:Delayed neuronal cell death largely contributes to the progressive infarct development and associated functional impairments after cerebral ischemia or brain trauma. Previous studies exposed a key role for the interaction of the mitochondrial protein apoptosis-inducing factor (AIF) and cytosolic cyclophilin A (CypA) in pathways of programmed cell death in neurons in vitro and in vivo. These studies suggested that pro-apoptotic activities of AIF, such as its translocation to the nucleus and subsequent DNA degradation, depend on the physical interaction of AIF with CypA. Hence, this protein complex may represent a new pharmacological target for inhibiting the lethal action of AIF on the brain tissue. In this study, we show that the AIF amino-acid residues 370-394 mediate the protein complex formation of AIF with CypA. The synthetic AIF(370-394) peptide inhibited AIF/CypA complex formation in vitro by binding CypA with a K(D) of 12 ?M. Further, the peptide exerted pronounced neuroprotective effects in a model of glutamate-induced oxidative stress in cultured HT-22 cells. In this model system of AIF-dependent cell death, the AIF(370-394) peptide preserved mitochondrial integrity, as detected by measurements of the mitochondrial membrane potential and quantification of mitochondrial fragmentation. Further, the AIF(370-394) peptide inhibited perinuclear accumulation of fragmented mitochondria, mitochondrial release of AIF to the nucleus and glutamate-induced cell death to a similar extent as CypA-siRNA. These data indicate that the targeting of the AIF-CypA axis is an effective strategy of neuroprotection.

| S-EPMC4040673 | biostudies-literature

Inhibition of monoamine oxidase by (E)-styrylisatin analogues.

Project description:Previous studies have shown that (E)-8-(3-chlorostyryl)caffeine (CSC) is a specific reversible inhibitor of human monoamine oxidase B (MAO-B) and does not bind to human MAO-A. Since the small molecule isatin is a natural reversible inhibitor of both MAO-B and MAO-A, (E)-5-styrylisatin and (E)-6-styrylisatin analogues were synthesized in an attempt to identify inhibitors with enhanced potencies and specificities for MAO-B. The (E)-styrylisatin analogues were found to exhibit higher binding affinities than isatin with the MAO preparations tested. The (E)-5-styrylisatin analogues bound more tightly than the (E)-6 analogue although the latter exhibits the highest MAO-B selectivity. Molecular docking studies with MAO-B indicate that the increased binding affinity exhibited by the (E)-styrylisatin analogues, in comparison to isatin, is best explained by the ability of the styrylisatins to bridge both the entrance cavity and the substrate cavity of the enzyme. Experimental support for this model is shown by the weaker binding of the analogues to the Ile199Ala mutant of human MAO-B. The lower selectivity of the (E)-styrylisatin analogues between MAO-A and MAO-B, in contrast to CSC, is best explained by the differing relative geometries of the aromatic rings for these two classes of inhibitors.

| S-EPMC2693004 | biostudies-literature

Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.

Project description:Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibition of the mitochondrial pyruvate carrier (MPC) protects primary cortical neurons from excitotoxic death. Reductions in mitochondrial pyruvate uptake do not compromise cellular energy metabolism, suggesting neuronal metabolic flexibility. Rather, MPC inhibition rewires mitochondrial substrate metabolism to preferentially increase reliance on glutamate to fuel energetics and anaplerosis. Mobilizing the neuronal glutamate pool for oxidation decreases the quantity of glutamate released upon depolarization and, in turn, limits the positive-feedback cascade of excitotoxic neuronal injury. The finding links mitochondrial pyruvate metabolism to glutamatergic neurotransmission and establishes the MPC as a therapeutic target to treat neurodegenerative diseases characterized by excitotoxicity.

| S-EPMC5379957 | biostudies-literature

DIDS protects against neuronal injury

Project description:Using long-oligo beadschip arrays, we examined the global gene expression profile in cultured hippocampal slices under the simulated ischemic condition with and without the presence of DIDS . Control-ACSF: cultured hippocampal slices were incubated with ACSF for 2 hours and were analysed on whole-genome expression chips to determine the gene expression profile. This group was used as controls for IS-treated groups and ACSF+DIDS-treated grous. IS: cultured hippocampal slices were treated wtih IS for 2 hours and the gene expression was analyzed and compared with the control group. IS+DIDS: cultured slices were treated with both IS and DIDS for 2 hours and the gene expression profile was determined. Differentially expression genes were identified by comparing with IS group. ACSF+DIDS: cultured slices were incubated with both ACSF and DIDS for 2 hours and gene expression profile was determined. This group was used as a control for IS+DIDS group. ACSF: artificial cerebral spinal fluid DIDS: 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid IS: ischemic solution

2010-05-15 | E-GEOD-12426 | biostudies-arrayexpress

Inhibition of Monoamine Oxidase by Stilbenes from Rheum palmatum.

Project description:Seven stilbenes and one catechin were bioactivity-guidedly isolated from the rhizomes of Rheum palmatem. Their structures were identified as piceatannol (1), resveratrol (2), piceid (3), rhapontigenin (4), piceatannol-3´-O-?-D-glucopyranoside (5), rhaponticin (6), catechin (7) and desoxyrhapontigenin (8). Anti-monoamine oxidase (MAO) activities of compounds 1-8 were tested. Compounds 1 and 8 showed significant MAO inhibitory activities with IC50 values 16.4 ± 1.5 ?M and 11.5 ± 1.1, respectively, when the IC50 value of iproniazid as a standard was 6.5 ± 0.5 ?M. The selectivity of compounds 1-8 against MAO-A and MAO-B were also evaluated. The results showed that compounds 4?6?8 preferred to inhibit MAO-A rather than MAO-B with selectivity values ([IC50 of MAO-B]/ [IC50 of MAO-A]) of 4.74, 10.01 and 9.42, respectively. The preliminary structure-activity relationships (SARs) of these compounds were discussed and the molecular modeling was also performed to explore the binding mode of inhibitors at the active site of MAO-A and MAO-B.

| S-EPMC5316268 | biostudies-literature

Furin inhibitor protects against neuronal cell death induced by activated NMDA receptors.

Project description:The proprotein convertases (PCs) act as serine proteases and are known to convert diverse precursor proteins into their active forms. Among the PCs, furin has been considered to play a crucial role not only in embryogenesis, but also in the initiation and progression of certain pathologic conditions. However, the roles played by furin with respect to neuronal cell injuries remain to be determined. An excessive influx of Ca2+ through the N-methyl-d-aspartate (NMDA) receptor has been associated with diverse neurological and neurodegenerative disorders. The aim of this study was to achieve further insight into the pathophysiologic roles of furin in cultured cortical neurons. We demonstrated that furin inhibitors dose-dependently prevented neuronal injury induced by NMDA treatment. Neuronal injury induced by NMDA treatment was attenuated by the calpain inhibitor calpeptin. And the increase observed in the activity of calpain after NMDA treatment was significantly inhibited by these furin inhibitors. Furthermore, calpain-2 activity, which was evaluated by means of the immunoblotting assay, was increased by NMDA treatment. It was noteworthy that this increased activity was almost completely inhibited by a furin inhibitor. Our findings suggested that furin is involved in NMDA-induced neuronal injury by acting upstream of calpain.

| S-EPMC5980093 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data