Abstract:
:Transcriptional dysregulation is a hallmark of Huntington's disease (HD) and one cause of this dysregulation is enhanced activity of the REST-mSIN3a-mSIN3b-CoREST-HDAC repressor complex, which silences transcription through REST binding to the RE1/NRSE silencer. Normally, huntingtin (HTT) prevents this binding, allowing expressing of REST target genes. Here, we aimed to identify HTT mimetics that disrupt REST complex formation in HD. From a structure-based virtual screening of 7 million molecules, we selected 94 compounds predicted to interfere with REST complex formation by targeting the PAH1 domain of mSIN3b. Primary screening using DiaNRSELuc8 cells revealed two classes of compounds causing a greater than two-fold increase in luciferase. In particular, quinolone-like compound 91 (C91) at a non-toxic nanomolar concentration reduced mSIN3b nuclear entry and occupancy at the RE1/NRSE within the Bdnf locus, and restored brain-derived neurotrophic factor (BDNF) protein levels in HD cells. The mRNA levels of other RE1/NRSE-regulated genes were similarly increased while non-REST-regulated genes were unaffected. C91 stimulated REST-regulated gene expression in HTT-knockdown Zebrafish and increased BDNF mRNA in the presence of mutant HTT. Thus, a combination of virtual screening and biological approaches can lead to compounds reducing REST complex formation, which may be useful in HD and in other pathological conditions.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Conforti P,Zuccato C,Gaudenzi G,Ieraci A,Camnasio S,Buckley NJ,Mutti C,Cotelli F,Contini A,Cattaneo Edoi
10.1111/jnc.12348subject
Has Abstractpub_date
2013-10-01 00:00:00pages
22-35issue
1eissn
0022-3042issn
1471-4159journal_volume
127pub_type
杂志文章abstract::We recently described a new protein associated exclusively with neuronal clathrin-coated vesicles (CCVs), and characterized two monoclonal antibodies that react with it (S-8G8 and S-6G7). In this report, the association of neuronal protein of 185 kilodaltons (NP185) with CCV kinases and its interaction with tubulin ar...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1989.tb10929.x
更新日期:1989-01-01 00:00:00
abstract::We have previously demonstrated hippocampal hyperglutamatergic signaling occurs prior to plaque accumulation in AβPP/PS1 mice. Here, we evaluate 2-Amino-6-(trifluoromethoxy) benzothiazole (riluzole) as an early intervention strategy for Alzheimer's disease (AD), aimed at restoring glutamate neurotransmission prior to ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.15224
更新日期:2020-10-26 00:00:00
abstract::Cell culture studies have shown that the Alzheimer amyloid precursor protein (APP) is secreted after full-length APP is cleaved by a putative secretase at the Lys16-Leu17 bond (secretase cleavage I) of the amyloid peptide sequence. Because this cleavage event is incompatible with amyloid production, it has been assume...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1992.tb10128.x
更新日期:1992-12-01 00:00:00
abstract::The protein B-50 is dephosphorylated in rat cortical synaptic plasma membranes (SPM) by protein phosphatase type 1 and 2A (PP-1 and PP-2A)-like activities. The present studies further demonstrate that B-50 is dephosphorylated not only by a spontaneously active PP-1-like enzyme, but also by a latent form after pretreat...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1992.tb08913.x
更新日期:1992-07-01 00:00:00
abstract::Extracts of rat tissues were subjected to ultracentrifugation on linear density gradients of sucrose (5-20%) and fractions of these gradients were analyzed for acetylcholinesterase (AChE) activity. Most of the AChE activity in extracts of vagus nerve was found to sediment at 10S. However, 16S AChE, previously thought ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1980.tb07870.x
更新日期:1980-11-01 00:00:00
abstract::GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain. Some of them are targets of benzodiazepines that are widely used in clinical practice for their sedative/hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects. In order to rationally separate these different drug actions, we...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2009.06419.x
更新日期:2009-12-01 00:00:00
abstract::Neural transplantation is an experimental treatment for Parkinson's disease. Widespread clinical application of the grafting technique is hampered by a relatively poor survival (around 10%) of implanted embryonic dopamine neurones. Earlier animal studies have indicated that a large proportion of the grafted cells die ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2003.01931.x
更新日期:2003-09-01 00:00:00
abstract::Apolipoprotein E (apoE) plays a crucial role in lipid transport in circulation and the brain. The apoE4 isoform is a major risk factor for Alzheimer's disease (AD). ApoE4 is more susceptible to proteolysis than other apoE isoforms and apoE4 fragments have been found in brains of AD patients. These apoE4 fragments have...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2010.06756.x
更新日期:2010-11-01 00:00:00
abstract::Glutamate receptor (GluR) δ1 is widely expressed in the developing forebrain, whereas GluRδ2 is selectively expressed in cerebellar Purkinje cells. Recently, we found that trans-synaptic interaction of postsynaptic GluRδ2 and pre-synaptic neurexins (NRXNs) through cerebellin precursor protein (Cbln) 1 mediates excitat...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2011.07631.x
更新日期:2012-06-01 00:00:00
abstract::Our results provide evidence that 6-hydroxydopamine induced, after auto-oxidation, toxic levels of hydrogen peroxide (H2O2) that caused bovine chromaffin cell toxicity and death. 6-Hydroxydopamine (6-OHDA) treatment markedly reduced, in a dose-response fashion, chromaffin cell viability. Cell death was accompanied by ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2003.01592.x
更新日期:2003-03-01 00:00:00
abstract::Spinal cord injury (SCI) elicits a neuroinflammatory reaction dominated by microglia and monocyte-derived macrophages (MDM). Because MDM do not infiltrate the spinal cord until days after injury, it may be possible to control whether they differentiate into neuroprotective or neurotoxic effector cells. However, doing ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2007.04617.x
更新日期:2007-08-01 00:00:00
abstract::As an initial step to study the function of the gene encoding the human neuropeptide FF (NPFF), we cloned a 4.7-kb sequence from the promoter region. Primer extension and 5'-rapid amplification of cDNA ends revealed multiple transcription initiation sites. Northern blot analysis of the mRNA expression revealed a speci...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2002.01035.x
更新日期:2002-09-01 00:00:00
abstract::The rapid bidirectional transport of dopamine beta-hydroxylase (DBH) in adrenergic axons provides a means of analyzing the life cycle of adrenergic storage vesicles. We compared the physical characteristics of DBH-containing particles traveling to or returning from the terminal varicosities of ligated rat sciatic nerv...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1989.tb07379.x
更新日期:1989-08-01 00:00:00
abstract::Thymosin beta 4 (Tβ4), a secreted 43 amino acid peptide, promotes oligodendrogenesis, and improves neurological outcome in rat models of neurologic injury. We demonstrated that exogenous Tβ4 treatment up-regulated the expression of the miR-200a in vitro in rat brain progenitor cells and in vivo in the peri-infarct are...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.13394
更新日期:2016-01-01 00:00:00
abstract::To assess maturation of central serotonin and catecholamine pathways at birth, we measured lumbar CSF homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), stable acid metabolites of dopamine and serotonin, using HPLC with electrochemical detection. CSFs from 57 neonates (38 premature and 19 at term) and 13...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1984.tb06109.x
更新日期:1984-12-01 00:00:00
abstract::The lipids of gastrocnemius muscle from normal and dystrophic (dy) mice of the Bar Harbor, 129Re strain were studied. Animals were fed diets containing either 3.1% or 1.1% of total calories as linoleic acid. Lipid analyses were also done on muscle from a new mouse mutant, A2G-adr, which has abnormal muscle function, c...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1985.tb05502.x
更新日期:1985-07-01 00:00:00
abstract::It is necessary for the cell-cycle machinery of neurons to be suppressed to promote differentiation and maintenance of their terminally differentiated state. Reactivation of the cell cycle in response to neurotoxic insults leads to neuronal cell death and some cell-cycle-related proteins contribute to the process. p27...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.13918
更新日期:2017-02-01 00:00:00
abstract::Both trafficking and secretion critically depend on accurate and specific membrane recognition and fusion. A key step in these processes is the assembly of a complex consisting of a small number of proteins, i.e., the exocytic core complex. In nerve terminals, this set consists of VAMP and synaptotagmin, which reside ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章,评审
doi:10.1046/j.1471-4159.1997.69051781.x
更新日期:1997-11-01 00:00:00
abstract::A combination of posttranslational modifications contributes to the high heterogeneity of brain tubulin in mammals. In this report, the structures of the detyrosinated carboxy-terminal peptides of alpha-tubulin from newborn and adult mouse brain were compared. The heterogeneity of these carboxy-terminal peptides was o...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1996.67052104.x
更新日期:1996-11-01 00:00:00
abstract::The neurotoxic properties of the dietary excitotoxins beta-N-methylamino-L-alanine and beta-N-oxalylamino-L-alanine have been studied in rat cerebellar granule cells and compared with those of glutamate. Glutamate caused dose-dependent death of cerebellar granule cells after a 30-min exposure when viability was assess...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1997.69041508.x
更新日期:1997-10-01 00:00:00
abstract::Female mice are more susceptible to apolipoprotein E (apoE4)-induced cognitive deficits than male mice. These deficits can be antagonized by stimulating androgen receptors (ARs). To determine the role of AR in the cognitive effects of apoE4, we backcrossed mutant mice with a naturally occurring defect in the AR [testi...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2007.05092.x
更新日期:2008-04-01 00:00:00
abstract::The parenteral administration of L-phenylalanine or p-tyrosine increases the mouse striatal concentration of p-tyramine, an effect that is enhanced by monoamine oxidase inhibition and reduced by an L-aromatic aminoacid decarboxylase inhibitor. Striatal m-tyramine was increased following administration of L-phenylalani...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1982.tb07971.x
更新日期:1982-09-01 00:00:00
abstract::Three fractions (one soluble and two membrane-bound) of choline acetyltransferase (ChAT) isolated from a nerve ending fraction of mouse forebrain, which have previously been reported to differ in several biochemical and physical aspects, were also found to differ in their rates of postnatal development. At 2 days of a...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1984.tb12815.x
更新日期:1984-09-01 00:00:00
abstract::2-Amino-4,5,6,7-tetrahydrobenzo(beta)thiophen-3-yl 4-chlorophenylmethanone (T62) is a member of a group of allosteric modulators of adenosine A1 receptors tested in animal models of neuropathic pain to increase the efficacy of adenosine. To determine its mechanisms at the level of receptor-G-protein activation, the pr...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2005.03044.x
更新日期:2005-05-01 00:00:00
abstract::Edaravone (Eda) is a potent scavenger of hydroxyl radicals and has been demonstrated to be beneficial for patients with acute ischemic stroke. This study was set out to investigate whether Eda protect against MPP(+)-induced cytotoxicity in rat primary cultured astrocytes. The results showed that pre-treatment with Eda...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2008.05573.x
更新日期:2008-09-01 00:00:00
abstract::Several members of the tetrahydroisoquinoline (TIQ) family of monoamine alkaloids can be formed from dopamine or its oxidized metabolites and may be involved in the pathogenesis of monoaminergic cell death in Parkinson's disease (PD). Using enantiomeric-selective high-performance liquid chromatography with electrochem...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2008.05709.x
更新日期:2008-12-01 00:00:00
abstract::The effects of heat stress on protein synthesis and fast axonal transport were examined in an in vitro bullfrog primary afferent neuron preparation. The magnitude of effect was determined for individual [35S]methionine-labelled protein species separated via two-dimensional gel electrophoresis. Elevation of temperature...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1988.tb01833.x
更新日期:1988-09-01 00:00:00
abstract::We studied the effects of 12-O-tetradecanoylphorbol 13-acetate (TPA), a protein kinase C (PKC) activator, and calyculin A (CLA), an inhibitor of type 1 and 2A serine/threonine phosphatases, on serotonin uptake by a human placenta choriocarcinoma cell line (BeWo) and COS-7 cells expressing recombinant serotonin transpo...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1997.68062618.x
更新日期:1997-06-01 00:00:00
abstract::We developed a rapid and sensitive radioimmunohistochemical method for the quantification of tyrosine hydroxylase (TH) at both the anatomical and cellular level. Coronal tissue sections from fresh-frozen rat brains were incubated in the presence of a TH monoclonal antibody. The reaction was revealed with a 35S-labeled...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1993.tb02166.x
更新日期:1993-08-01 00:00:00
abstract::The distributions of glutamate decarboxylase (EC 4.1.1.15), gamma-aminobutyric acid transaminase (EC 2.6.1.19), and succinate semialdehyde dehydrogenase (EC 1.2.1.24) were determined in monkey retina. The decarboxylase was almost restricted to the inner plexiform layer. The transaminase was also highest in this layer,...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1984.tb02782.x
更新日期:1984-05-01 00:00:00