Abstract:
:The olfactory bulb is one of the most vulnerable brain regions in age-related proteinopathies. Proteinopathic stress is mitigated by the heat shock protein (Hsp) family of chaperones. Here, we describe age-related decreases in Hsc70 in the olfactory bulb of the female rat and higher levels of Hsp70 and Hsp25 in middle and old age than at 2-4 months. To model proteotoxic and oxidative stress in the olfactory bulb, primary olfactory bulb cultures were treated with the proteasome inhibitors lactacystin and MG132 or the pro-oxidant paraquat. Toxin-induced increases were observed in Hsp70, Hsp25, and Hsp32. To determine the functional consequences of the increase in Hsp70, we attenuated Hsp70 activity with two mechanistically distinct inhibitors. The Hsp70 inhibitors greatly potentiated the toxicity of sublethal lactacystin or MG132 but not of paraquat. Although ubiquitinated protein levels were unchanged with aging in vivo or with sublethal MG132 in vitro, there was a large, synergistic increase in ubiquitinated proteins when proteasome and Hsp70 functions were simultaneously inhibited. Our study suggests that olfactory bulb cells rely heavily on Hsp70 chaperones to maintain homeostasis during mild proteotoxic, but not oxidative insults, and that Hsp70 prevents the accrual of ubiquitinated proteins in these cells. The olfactory bulb is affected in the early phases of many age-related neurodegenerative disorders. Here, we described the impact of aging on multiple heat shock proteins (Hsps), such as Hsp70, in the female rat olfactory bulb in vivo. Using multiple proteasome and Hsp70 inhibitors (see schematic), we found that proteotoxicity elicited a compensatory increase in Hsp70 in primary olfactory bulb cells in vitro. Hsp70 then reduced the proteotoxic buildup of ubiquitinated proteins and robustly protected against cell death according to three independent viability assays. Thus, olfactory bulb neurons can mount impressive natural adaptations to proteotoxic injury, perhaps explaining why neurodegenerative disorders are so delayed in onset and so slow to progress.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Crum TS,Gleixner AM,Posimo JM,Mason DM,Broeren MT,Heinemann SD,Wipf P,Brodsky JL,Leak RKdoi
10.1111/jnc.13041subject
Has Abstractpub_date
2015-06-01 00:00:00pages
780-794issue
6eissn
0022-3042issn
1471-4159journal_volume
133pub_type
杂志文章abstract::Abstract Huntingtin is a large, multi-domain protein of unknown function in the brain. An abnormally elongated polyglutamine stretch in its N-terminus causes Huntington's disease (HD), a progressive neurodegenerative disorder. Huntingtin has been proposed to play a functional role in membrane trafficking via proteins ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2005.03620.x
更新日期:2006-02-01 00:00:00
abstract::The ubiquitous second messenger cyclic GMP (cGMP) is synthesized by soluble guanylate cyclases in response to nitric oxide (NO) and degraded by phosphodiesterases (PDE). We studied the homeostasis of cGMP in living thalamic neurons by using the genetically encoded fluorescence resonance energy transfer sensor Cygnet, ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2007.04657.x
更新日期:2007-09-01 00:00:00
abstract::The capacity of D1 and D2 agonists and antagonists to regulate the in vivo release and metabolism of dopamine (DA) in mesolimbic and nigrostriatal DA neurons of the mouse was determined using gas chromatographic and mass fragmentographic (GC-MF) analysis. DA release was inferred from levels of 3-methoxytyramine (3-MT)...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1987.tb05591.x
更新日期:1987-03-01 00:00:00
abstract::Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by an expansion of the polyglutamine tract near the C-terminus of the MJD-1 gene product, ataxin-3. Ataxin-3 is degraded by the proteasome. However, the precise mechanism of ataxin-3 degradation remains to be elucidated. In this st...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2007.04460.x
更新日期:2007-06-01 00:00:00
abstract::Stem cell-based approaches provide hope as a potential therapy for neurodegenerative diseases and stroke. One of the major scientific hurdles for stem cell therapy is the poor survival rate of the newly formed or transplanted neural stem cells. In this study, we found that low-dose treatment with the Heat shock protei...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2011.07239.x
更新日期:2011-05-01 00:00:00
abstract::Axonal degeneration is a key component of many neurodegenerative diseases. Injured axons undergo a program of self-destruction termed Wallerian degeneration that is an active, well-regulated process. The pathways leading to axon fragmentation are uncharacterized, but experiments with wld(s) mutant mice led to the disc...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2009.06002.x
更新日期:2009-04-01 00:00:00
abstract::Binding of DL-alpha-[3H]amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ([3H]AMPA) to lysed rat brain membranes in the presence of potassium thiocyanate resulted in curvilinear Scatchard plots that could be resolved by regression analysis into a large low-affinity component and a small high-affinity component. Sol...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1992.tb10086.x
更新日期:1992-12-01 00:00:00
abstract::The amygdala has been implicated in the neuronal sequelae of stress, although little is known about the neurochemical mechanisms underlying amygdala transmission. In vivo microdialysis was employed to measure extracellular levels of dopamine in the basolateral nucleus of the amygdala in awake rats. Once it was establi...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1999.0721088.x
更新日期:1999-03-01 00:00:00
abstract::The biotransformation of the opioid peptide dynorphin A(1-17) was investigated in striatum of freely moving Fischer rats, by direct infusion of this peptide, followed by recovery of the resulting biotransformation products via microdialysis and identification using matrix-assisted laser desorption/ionization mass spec...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2003.01859.x
更新日期:2003-08-01 00:00:00
abstract::The antagonistic effects of gallamine on muscarinic receptor-linked responses were investigated in N1E-115 neuroblastoma cells. M1 muscarinic receptor-mediated phosphoinositide hydrolysis induced by carbamylcholine was antagonized by gallamine, with a Ki value of 33 microM. By comparison, gallamine was four- to fivefo...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1989.tb07428.x
更新日期:1989-10-01 00:00:00
abstract::Progression of α-synuclein inclusion pathology may occur through cycles of release and uptake of α-synuclein aggregates, which induce additional intracellular α-synuclein inclusion pathology. This process may explain (i) the presence of α-synuclein inclusion pathology in grafted cells in human brains, and (ii) the slo...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.13743
更新日期:2017-02-01 00:00:00
abstract::The human NMDAR2D subunit was cloned, and the pharmacological properties of receptors resulting from injection of transcripts encoding human NMDAR1A and NMDAR2D subunits in Xenopus oocytes were characterized by profiling NMDA receptor agonists and antagonists. We found that glutamate, NMDA, glycine, and D-serine were ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1998.70031269.x
更新日期:1998-03-01 00:00:00
abstract::In the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the walls of the lateral ventricles, and the subgranular zone of the hippocampus, which generate new neurons for the olfactory bulb and dentate gyrus, respectively. These adult NSCs retain their self-renewal ability and capacity t...
journal_title:Journal of neurochemistry
pub_type: 杂志文章,评审
doi:10.1111/jnc.14557
更新日期:2018-12-01 00:00:00
abstract::Increasing evidence suggests that the dopaminergic degeneration which characterizes Parkinson's disease starts in the striatal dopamine terminals and progresses retrogradely to the body of dopamine cells in the substantia nigra. The role of striatal astrocytes in the striatal initiation of the dopaminergic degeneratio...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.13684
更新日期:2016-10-01 00:00:00
abstract::Cultures of bovine adrenomedullary chromaffin cells accumulated 1-[methyl-3H]methyl-4-phenylpyridinium ([3H]MPP+) in a time- and concentration-dependent manner with an apparent Km of 0.7 microM and a Vmax of 3 pmol/min/10(6) cells. The uptake was sodium dependent and sensitive to inhibitors of the cell-surface catecho...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1989.tb01873.x
更新日期:1989-04-01 00:00:00
abstract::SH-SY5Y neural cells expressing mu- and delta-opioid receptors were maintained viable in isotonic, sodium-free buffer in vitro. Intracellular sodium levels were manipulated by various methods, and ligand binding to intact cells was studied. In physiological buffer containing 118 mM sodium, [3H]Tyr-D-Ala-Gly-(Me)Phe-Gl...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1997.68031053.x
更新日期:1997-03-01 00:00:00
abstract::Previous studies examining age differences in membrane fluidity and cholesterol content have reported on the average or total change in membrane structure, respectively. However, a membrane consists of an exofacial leaflet and a cytofacial leaflet that differ in fluidity and cholesterol distribution. The purpose of th...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1996.66041717.x
更新日期:1996-04-01 00:00:00
abstract::The effect of manipulating the activity of central 5-hydroxytryptamine (5-HT) neurones on extracellular 5-HT in ventral hippocampus of the chloral hydrate-anaesthetized rat was studied using the brain perfusion method, microdialysis. Basal levels of 5-HT in the dialysates were close to the detection limits of our assa...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1989.tb07319.x
更新日期:1989-07-01 00:00:00
abstract::Benzodiazepine receptor binding was measured in cerebellar cortex of 15 patients with dominantly inherited olivopontocerebellar atrophy (OPCA). The majority of these patients had a moderate to marked Purkinje cell loss, as judged by the lowered levels of dentate nucleus gamma-aminobutyric acid (GABA), a marker of Purk...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1984.tb02700.x
更新日期:1984-02-01 00:00:00
abstract::Dibutyryl cyclic AMP (dBcAMP) is known to induce maturation and differentiation in astrocytes. As myo-inositol is an important osmoregulator in astrocytes, we examined the effects of maturation and biochemical differentiation on the kinetic properties of myo-inositol transport. Treatment of astrocytes with dBcAMP sign...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1999.0730105.x
更新日期:1999-07-01 00:00:00
abstract::Math2 (NEX-1/NeuroD6) is a member of the basic helix-loop-helix transcription factor family and is involved in neuronal differentiation and maturation. In this study, we identified the genes targeted by Math2 using DNA microarrays and cultured rat cortical cells transfected with Math2. Of the genes regulated by Math2,...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2008.05579.x
更新日期:2008-09-01 00:00:00
abstract::Phosphodiesterase (PDE) 7B, a cAMP-specific PDE which is dominantly expressed in striatum, is expected to be involved in dopaminergic signaling in striatal neurons. Here we show, for the first time, the involvement of the dopaminergic signaling pathway in transcriptional activation of rat PDE7B in primary striatal cul...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2004.02354.x
更新日期:2004-04-01 00:00:00
abstract::Myelin P2 protein is a small (14,800 Da) protein found in peripheral and central nervous system myelin. To investigate the regulation of expression of this myelin protein, a mouse genomic library was screened with a rabbit P2 cDNA (pSN2.2-2), and a single positive phage clone containing a 20-kb insert was obtained. Th...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1991.tb02101.x
更新日期:1991-07-01 00:00:00
abstract::Corticotropin-releasing factor (CRF) stimulates rat retinal adenylate cyclase activity in a concentration-dependent manner. The half-maximal effect is obtained at 50 nM CRF and the maximal stimulation corresponds to approximately 90% increase of basal enzyme activity. The CRF effect is counteracted by the CRF antagoni...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1990.tb04899.x
更新日期:1990-06-01 00:00:00
abstract::In this study, we show specific intracellular responses evoked by the stimulation of astrocytes with the P1,P5-di(adenosine-5')pentaphosphate, Ap5A. The stimulation of astrocytes with micromolar concentrations of the dinucleotide elicited rapid increases in intracellular calcium concentration ([Ca2+]i), showing an EC5...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2002.01111.x
更新日期:2002-10-01 00:00:00
abstract::We designed as candidate metabolites and synthesized two 1-benzyl-1,2,3,4-tetrahydroisoquinoline derivatives containing a dopamine moiety: 1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3',4'DHBnTIQ) and 1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (6,7DHBnTIQ). Both were detected in mouse brain as...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1998.70020745.x
更新日期:1998-02-01 00:00:00
abstract::Free radicals have been implicated in the etiology of many neurodegenerative conditions. Yet, because these species are highly reactive and thus short-lived it has been difficult to test these hypotheses. We adapted a method in which hydroxyl radicals are trapped by salicylate in vivo, resulting in the stable and quan...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1995.64041819.x
更新日期:1995-04-01 00:00:00
abstract::Endogenous norepinephrine (NE) release in cerebral cortex slices taken from normal and morphine-tolerant guinea pigs was measured by HPLC. In normal slices, a linear relationship was found between electrically evoked NE release and the log of the frequency of stimulation in the range of 1-20 Hz. The efficiency of the ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1992.tb11361.x
更新日期:1992-04-01 00:00:00
abstract::Niemann-Pick type C disease (NPCD) was first described in 1914 and affects approximately 1 in 150 000 live births. It is characterized clinically by diverse symptoms affecting liver, spleen, motor control, and brain; premature death invariably results. Its molecular origins were traced, as late as 1997, to a protein o...
journal_title:Journal of neurochemistry
pub_type: 杂志文章,评审
doi:10.1111/jnc.14895
更新日期:2020-06-01 00:00:00
abstract::Activation of cAMP signaling pathway and its transcriptional factor cyclic AMP response element binding protein (CREB) and coactivator are key determinants of neuronal differentiation and plasticity. We show that nuclear fibroblast growth factor receptor-1 (FGFR1) mediates cAMP-induced neuronal differentiation and reg...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2003.01624.x
更新日期:2003-03-01 00:00:00