Abstract：
:The genetic defect in Friedreich's ataxia (FRDA) is the expansion of a GAA·TCC triplet in the first intron of the FXN gene, which encodes the mitochondrial protein frataxin. Previous studies have established that the repeats reduce transcription of this essential gene, with a concomitant decrease in frataxin protein in affected individuals. As the repeats do not alter the FXN protein coding sequence, one therapeutic approach would be to increase transcription of pathogenic FXN genes. Histone posttranslational modifications near the expanded repeats are consistent with heterochromatin formation and FXN gene silencing. In an effort to find small molecules that would reactivate this silent gene, histone deacetylase inhibitors were screened for their ability to up-regulate FXN gene expression in patient cells and members of the pimelic 2-aminobenzamide family of class I histone deacetylase inhibitors were identified as potent inducers of FXN gene expression and frataxin protein. Importantly, these molecules up-regulate FXN expression in human neuronal cells derived from patient-induced pluripotent stem cells and in two mouse models for the disease. Preclinical studies of safety and toxicity have been completed for one such compound and a phase I clinical trial in FRDA patients has been initiated. Furthermore, medicinal chemistry efforts have identified improved compounds with superior pharmacological properties.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Gottesfeld JM,Rusche JR,Pandolfo Mdoi
10.1111/jnc.12302subject
Has Abstractpub_date
2013-08-01 00:00:00pages
147-54eissn
0022-3042issn
1471-4159journal_volume
126 Suppl 1pub_type
杂志文章,评审abstract：:Tryptophan hydroxylase (TPH) is the initial and rate-limiting enzyme in serotonin biosynthesis. The enzyme activity is dependent on molecular oxygen, a tetrahydropterin cosubstrate, and ferrous iron. The present study demonstrates that TPH is inhibited by a novel compound, p-ethynylphenylalanine (pEPA), produced by th...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2000.0742067.x
更新日期：2000-05-01 00:00:00
abstract：:To determine whether prolonged nicotine exposure persistently inactivates rat alpha4beta2 nicotinic receptors expressed in Xenopus oocytes, we measured the voltage-clamped alpha4beta2 response to acetylcholine (ACh) before and 24 h after, 1-h or 12-h incubations in 10 microm nicotine. A 12-h incubation in 10 microm ni...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2003.01578.x
更新日期：2003-02-01 00:00:00
abstract：:The objective of this study was to examine the role of dopamine (DA) receptors in the nucleus accumbens (ACB) in controlling feedback regulation of mesolimbic somatodendritic DA release in the ventral tegmental area (VTA) of Wistar rats using ipsilateral dual-probe in vivo microdialysis. Perfusion of the ACB for 60 mi...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2000.740684.x
更新日期：2000-02-01 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：:A sensitive enzyme-linked immunosorbent assay (ELISA) for nerve growth factor (NGF) has been developed. The sensitivity of this assay (0.1 pg/well) permits the quantification of endogenous immunoreactive NGF in the peripheral nervous system and the CNS. Studies on the regulatory mechanisms involved in NGF production i...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1987.tb05736.x
更新日期：1987-06-01 00:00:00
abstract：:The chemokine IL-8 is known to be synthesized by glial cells in the brain. It has traditionally been shown to have an important role in neuroinflammation but recent evidence indicates that it may also be involved in rapid signaling in neurons. We investigated how IL-8 participates in rapid neuronal signaling by using ...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2001.00469.x
更新日期：2001-09-01 00:00:00
abstract：:Fever is thought to be mediated by leukocytic pyrogen (LP), a polypeptide synthesized by phagocytic leukocytes and which is responsible for the upwards resetting of the hypothalamic thermostat. In an attempt to study the effects of LP directly on brain tissue, purified human LP was incubated with rabbit brain slices i...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1982.tb12544.x
更新日期：1981-09-01 00:00:00
abstract：:The administration of nicotine activates tyrosine hydroxylase in the rat adrenal gland. This activation is apparently maximal 25 min after a single subcutaneous injection of nicotine at 2.3 mg/kg. Repeated injections of nicotine (seven injections once every 30 min) are associated with a persistent activation of adrena...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1991.tb06424.x
更新日期：1991-12-01 00:00:00
abstract：:Glutamine is a primary precursor for the biosynthesis of the neurotransmitters glutamate and gamma-aminobutyric acid. It is proposed that glutamine, synthesized and released by astrocytes, is transported into the neuron for subsequent conversion to neurotransmitters. To provide a more complete characterization of this...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1997.68030954.x
更新日期：1997-03-01 00:00:00
abstract：:Monoclonal antibody BM88 recognizes a neurospecific surface antigen in the CNS and the PNS. In the present study, the antigen recognized by BM88 was immunopurified from pig brain and shown to be a 22-kDa polypeptide by reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Under nonreducing conditions a p...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1991.tb01992.x
更新日期：1991-03-01 00:00:00
abstract：:Aromatic L-amino acid decarboxylase (AAAD) activity of the rat retina increases when animals are placed in a lighted environment from the dark. The rise of activity can be inhibited by administering alpha 2 adrenoceptor agonists. In the dark, the enzyme activity can be made to increase by administering alpha 2 adrenoc...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1989.tb09169.x
更新日期：1989-02-01 00:00:00
abstract：:Rho family GTPases promote the survival of certain neuronal populations. However, pro-survival and pro-death signaling pathways regulated downstream of Rho GTPases are largely unknown. Cerebellar granule neurons (CGNs) exposed to Clostridium difficile toxin B (ToxB), a monoglucosyltransferase that specifically inhibit...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2006.03802.x
更新日期：2006-05-01 00:00:00
abstract：:Ligand binding to the cannabinoid receptor of brain membranes has been characterized using [3H]CP 55,940 and the Multiscreen Filtration System. Binding of [3H]CP 55,940 is saturable and reaches equilibrium by 45 min at room temperature. At a concentration of 10 micrograms of membrane protein/well, the KD for [3H]CP 55...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1995.64020677.x
更新日期：1995-02-01 00:00:00
abstract：:Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder for which no curative therapy is available. The cause of this disease is the expansion of a CAG repeat in the so-called ATXN3 gene leading to an expanded polyglutamine stretch in the ataxin-3 protein. Although the func...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/jnc.13606
更新日期：2016-07-01 00:00:00
abstract：:To evaluate the ability of ependymal, microglial and oligodendroglial cells to degrade leucine, the presence of 3-methylcrotonyl-CoA carboxylase (MCC) was investigated in cultures of these cells. MCC is a biotin-containing heterodimeric enzyme that is specific for the irreversible part of the leucine catabolic pathway...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2006.03819.x
更新日期：2006-06-01 00:00:00
abstract：:Quinolinic acid (QA) has been shown to evoke neurotoxic events via NMDA receptor (NMDAR) overactivation and oxidative stress. NMDARs are particularly vulnerable to free radicals, which can modulate protein tyrosine kinase (PTK) and phosphotyrosine phosphatase (PTP) activities. The src family of tyrosine kinases are as...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2006.03814.x
更新日期：2006-06-01 00:00:00
abstract：:Early onset familial Alzheimer's disease (FAD) is linked to autosomal dominant mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2) genes. These are critical mediators of total amyloid beta-peptide (Abeta) production, inducing cell death through uncertain mechanisms. Tauroursodeoxychol...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2006.04007.x
更新日期：2006-09-01 00:00:00
abstract：:Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors have been shown to modulate the morphology of the lamelar processes of Bergmann glia cells in the molecular layer of the cerebellum. Here we suggest that reorganization of F-actin may underlay the changes in the morphology of the lamelar proc...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/jnc.14658
更新日期：2019-04-01 00:00:00
abstract：:The nucleoside transporter of cerebral microvessels and choroid plexus was identified and characterized using [3H]nitrobenzylthioinosine (NBMPR) as a specific probe. [3H]NBMPR bound reversibly and with high affinity to a single specific site in particulate fractions of cerebral microvessels, choroid plexus, and cerebr...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1986.tb13098.x
更新日期：1986-12-01 00:00:00
abstract：:The effect of N-methyl-D-aspartate (NMDA) receptor antagonists on cell viability was studied in rat primary cortical cells. NMDA antagonists [MK-801 and 2-amino-5-phosphonovalerate (APV)] induced cell shrinkage, nuclear condensation or fragmentation, and internucleosomal DNA fragmentation. Treatment of cells with MK-8...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1999.0730548.x
更新日期：1999-08-01 00:00:00
abstract：:The cleavage-product of amyloid precursor protein (APP) constitutes the core component of plaques found in the brains of Alzheimer's disease (AD) patients. APP is ubiquitously expressed and its precise physiological functions remain unclear. This protein has been proposed to regulate synaptic function and processes un...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2007.04672.x
更新日期：2007-09-01 00:00:00
abstract：:In this study, we describe a novel form of anti-homeostatic plasticity produced after culturing spinal neurons with strychnine, but not bicuculline or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Strychnine caused a large increase in network excitability, detected as spontaneous synaptic currents and calcium transient...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2006.04306.x
更新日期：2007-03-01 00:00:00
abstract：:Carboxypeptidase E (CPE) functions in the posttranslational processing of bioactive peptides. Like other peptide processing enzymes, CPE is initially produced as a precursor ("proCPE") that undergoes posttranslational processing at a site containing five adjacent Arg residues near the N-terminus and at other sites nea...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1995.65010444.x
更新日期：1995-07-01 00:00:00
abstract：:Calcium-activated neutral proteases (calpains) are regulated by specific endogenous protein inhibitors, the calpastatins, which are widely distributed in mammalian tissues. Calpastatins from different species or in various tissues from the same species exhibit considerable size heterogeneity on sodium dodecyl sulfate ...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1995.64020859.x
更新日期：1995-02-01 00:00:00
abstract：:A sustained increase in the brain concentrations of neuroactive steroids was previously shown to induce Y1 receptor gene expression in the amygdala of Y1R/LacZ transgenic mice which harbour a construct comprising the murine Y1 receptor gene promoter and the lacZ reporter gene. We now investigated the effects of restra...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2004.02444.x
更新日期：2004-06-01 00:00:00
abstract：:Stressful stimuli induce two distinct cellular reactions, the heat-shock (stress) response and programmed cell death. This study utilizes a dual procedure involving immunocytochemistry for heat-shock protein localization and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2005.03591.x
更新日期：2006-04-01 00:00:00
abstract：:A rapid and simple chromatographic procedure using HPLC with electrochemical detection is described for simultaneous determination of the substrates from precursor amino acids to metabolites related to synthesis and metabolism of three monoamine neurotransmitters--norepinephrine (NE), dopamine (DA), and 5-hydroxytrypt...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.1988.tb02935.x
更新日期：1988-02-01 00:00:00
abstract：:The nervous tissue-specific protein B-50 (GAP-43), which has been implicated in the regulation of neurotransmitter release, is a member of a family of atypical calmodulin-binding proteins. To investigate to what extent calmodulin and the interaction between B-50 and calmodulin are involved in the mechanism of Ca(2+)-i...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1996.66051933.x
更新日期：1996-05-01 00:00:00
abstract：:Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large p...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1111/j.1471-4159.2005.03565.x
更新日期：2006-03-01 00:00:00
abstract：:We have previously reported that insulin/insulin-like growth factor (IGF)-I induced the alpha 1 isoform of Na+,K(+)-ATPase in cultured astrocytes. In this study the effects of insulin/IGF-I on Na+,K(+)-ATPase activity and cell proliferation were examined in astrocytes cultured under the various conditions, to test the...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.1996.66020511.x
更新日期：1996-02-01 00:00:00
