Journal of Neurochemistry (J NEUROCHEM)

Publisher: International Society for Neurochemistry, Wiley

Journal description

The Journal of Neurochemistry is the leading source for current research worldwide on the molecular chemical and cellular biology of the nervous system. Each issue contains dozens of full-length presentations of significant original findings written by investigators at leading medical and research institutions around the world. The Journal of Neurochemistry is devoted to the prompt publication of high-quality original findings in areas relevant to molecular chemical and cell biological aspects of the nervous system. Papers that are wholly pharmalogical histochemical or immunological and methods papers or the cloning of confirmatory sequences that do not advance knowledge in neurochemistry are not normally considered. The Journal particularly encourages submissions in the areas of molecular and cellular biology. A highlight of each issue is the Journal's critically acclaimed Rapid Communications section presenting new ideas and data of particular importance and timeliness. The Journal's Mini-Reviews present concise self-contained summaries of current research in particularly important areas.

Current impact factor: 4.28

Impact Factor Rankings

2016 Impact Factor Available summer 2017
2014 / 2015 Impact Factor 4.281
2013 Impact Factor 4.244
2012 Impact Factor 3.973
2011 Impact Factor 4.061
2010 Impact Factor 4.337
2009 Impact Factor 3.999
2008 Impact Factor 4.5
2007 Impact Factor 4.451
2006 Impact Factor 4.26
2005 Impact Factor 4.604
2004 Impact Factor 4.824
2003 Impact Factor 4.825
2002 Impact Factor 4.969
2001 Impact Factor 4.834
2000 Impact Factor 4.9
1999 Impact Factor 4.906
1998 Impact Factor 4.651
1997 Impact Factor 4.234
1996 Impact Factor 4.219
1995 Impact Factor 4.852
1994 Impact Factor 4.525
1993 Impact Factor 4.223
1992 Impact Factor 4.215

Impact factor over time

Impact factor

Additional details

5-year impact 3.97
Cited half-life 9.60
Immediacy index 1.00
Eigenfactor 0.05
Article influence 1.20
Website Journal of Neurochemistry website
Other titles Journal of neurochemistry, JNC
ISSN 0022-3042
OCLC 1782775
Material type Periodical, Internet resource
Document type Journal / Magazine / Newspaper, Internet Resource

Publisher details


  • Pre-print
    • Author can archive a pre-print version
  • Post-print
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  • Restrictions
    • 12 months embargo
  • Conditions
    • Some journals have separate policies, please check with each journal directly
    • On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network
    • Author's pre-print may not be updated with Publisher's Version/PDF
    • Author's pre-print must acknowledge acceptance for publication
    • Non-Commercial
    • Publisher's version/PDF cannot be used
    • Publisher source must be acknowledged with citation
    • Must link to publisher version with set statement (see policy)
    • If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Nuclear factor of activated T-cells (NFAT) is a family of transcription factors comprising four calcium-regulated members: NFATc1, NFATc2, NFATc3, and NFATc4. Upon activation by the calcium-dependent phosphatase calcineurin (CaN), NFATs translocate from cytosol to the nucleus and regulate their target genes, which in the nervous system are involved in axon growth, synaptic plasticity and neuronal survival. We have shown previously that there are a number of different splice variants of NFAT genes expressed in the brain. Here, we studied the subcellular localizations and transactivation capacities of alternative human NFAT isoforms in rat primary cortical or hippocampal neurons in response to membrane depolarization and compared the induced transactivation levels in neurons to those obtained from HEK293 cells in response to calcium signaling. We confirm that in neurons the translocation to the nucleus of all NFAT isoforms is reliant on the activity of CaN. However, our results suggest that both the regulation of subcellular localization and transcriptional activity of NFAT proteins in neurons is isoform-specific. We show that in primary hippocampal neurons NFATc2 isoforms have very fast translocation kinetics whereas NFATc4 isoforms translocate relatively slowly to the nucleus. Moreover, we demonstrate that the strongest transcriptional activators in HEK293 cells are NFATc1 and NFATc3 but in neurons NFATc3 and NFATc4 lead to the highest induction, and NFATc2 and NFATc1 display isoform-specific transcription activation capacities. Altogether, our results indicate that the effects of calcium signaling on the action of NFAT proteins are isoform-specific and can differ between cell types. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Journal of Neurochemistry
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    ABSTRACT: Glutamate signaling is achieved by an elaborate network involving neurons and astrocytes. Hence, it is critical to better understand how neurons and astrocytes interact to coordinate the cellular regulation of glutamate signaling. In these studies, we used rat cortical cell cultures to examine whether neurons or releasable neuronal factors were capable of regulating system xc (-) (Sxc), a glutamate releasing mechanism that is expressed primarily by astrocytes and has been shown to regulate synaptic transmission. We found that astrocytes cultured with neurons or exposed to neuronal conditioned media displayed significantly higher levels of Sxc activity. Next, we demonstrated that the pituitary adenylate cyclase-activating polypeptide (PACAP) may be a neuronal factor capable of regulating astrocytes. In support, we found that PACAP expression was restricted to neurons, and that PACAP receptors were expressed in astrocytes. Interestingly, blockade of PACAP receptors in cultures comprised of astrocytes and neurons significantly decreased Sxc activity to the level observed in purified astrocytes, while application of PACAP to purified astrocytes increased Sxc activity to the level observed in cultures comprised of neurons and astrocytes. Collectively, these data reveal that neurons coordinate the actions of glutamate-related mechanisms expressed by astrocytes such as Sxc, a process that likely involves PACAP. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Journal of Neurochemistry
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    ABSTRACT: The aggregation of alpha synuclein (α-syn) is a neuropathological feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated α-syn is the primary component of Lewy Bodies, the defining pathological feature of PD, while mutations or multiplications in the α-syn gene result in familial PD. The high correlation between α-syn burden and PD has led to the hypothesis that α-syn aggregation produces toxicity through a gain-of-function mechanism. However, α-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of α-syn results in toxicity due to a toxic loss of necessary α-syn function, following sequestration of functional forms α-syn into insoluble protein aggregates. Within this review we will provide an overview of the literature linking α-syn to PD and the knowledge gained from current α-syn-based animal models of PD. We will then interpret these data from the viewpoint of the α-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of α-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Journal of Neurochemistry
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    ABSTRACT: Postoperative cognitive decline (POCD) is a common geriatric complication, and sevoflurane is a widely accepted inducer of POCD. Although the aetiology of POCD is not clear, a breach in the blood-brain barrier (BBB) is involved in early POCD. Annexin A1 has shown protective effects on BBB function. The objective of the present study was to investigate both the effects of sevoflurane on the components of the BBB and the underlying mechanism. In vivo treatment with 3.6% sevoflurane for 6 h disrupted BBB components led to fibrinogen invasion and down-regulation of Annexin A1 expression at 24 h after inhalation. The administration of human recombinant Annexin A1 (hr Annexin A1) attenuated the disruption of BBB components, thereby reducing fibrinogen invasion. In addition, the administration of hr Annexin A1 improved cognitive function after the inhalation of 3.6% sevoflurane for 6 h. Moreover, in cultured endothelial cells, 3.6% sevoflurane for 6 h increased GSK-3β and decreased β-catenin levels at 24 h after inhalation. The activation/inhibition of the Wnt/β-catenin signalling pathway attenuated/worsened the sevoflurane-induced decrease in Annexin A1. Our findings indicate that in endothelial cells, treatment with 3.6% sevoflurane for 6 h inhibits the Wnt/β-catenin signalling pathway, thereby increasing GSK-3β and decreasing β-catenin. By inhibiting this pathway, the gas anaesthetic sevoflurane down-regulated Annexin A1, which consequently breached the BBB and induced POCD. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Journal of Neurochemistry

  • No preview · Article · Feb 2016 · Journal of Neurochemistry
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    ABSTRACT: This article is a critique of the paper by Khairnar et al. in the current issue of the Journal of Neurochemistry which describes the use of a sophisticated magnetic resonance imaging technique, diffusion kurtosis imaging, to investigate microstructural changes in the brain of TNWT-61 mice that are over-expressing α-synuclein. The importance of α-synuclein to Parkinson's disease pathology is considered and the article critically assessed. The steps needed to establish this method as a biomarker in human disease is discussed. Read the highlighted article 'Late-stage α-synuclein accumulation in TNWT-61 mouse model of Parkinson's disease detected by diffusion kurtosis imaging' on doi: 10.1111/jnc.13500.
    No preview · Article · Feb 2016 · Journal of Neurochemistry
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    ABSTRACT: Glutathione (GSH) is a tripeptide often considered to be the master antioxidant in cells. GSH plays an integral role in cellular redox regulation and is also known to have a role in mammalian copper homeostasis. In vitro evidence suggests that GSH is involved in copper uptake, sequestration and efflux. This study was undertaken to further investigate the roles that GSH plays in neuronal copper homeostasis in vivo, using the model organism Drosophila melanogaster. RNA interference-mediated knockdown of the Glutamate-cysteine ligase catalytic subunit gene (Gclc) that encodes the rate-limiting enzyme in GSH biosynthesis, was utilised to genetically deplete GSH levels. When Gclc was knocked down in all neurons, this caused lethality, which was partially rescued by copper supplementation and was exacerbated by additional knockdown of the copper uptake transporter Ctr1A, or overexpression of the copper efflux transporter ATP7. Furthermore, when Gclc was knocked down in a subset of neuropeptide-producing cells, this resulted in adult progeny with unexpanded wings, a phenotype previously associated with copper dyshomeostasis. In these cells, Gclc suppression caused a decrease in axon branching, a phenotype further enhanced by ATP7 overexpression. Therefore we conclude that GSH may play an important role in regulating neuronal copper levels and that reduction in GSH may lead to functional copper deficiency in neurons in vivo. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Journal of Neurochemistry
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    ABSTRACT: Human immunodeficiency virus-1 (HIV) promotes synaptic simplification and neuronal apoptosis, and causes neurological impairments termed HIV-associated neurological disorders (HAND). HIV-associated neurotoxicity may be brought about by acute and chronic mechanisms that still remain to be fully characterized. The HIV envelope glycoprotein gp120 causes neuronal degeneration similar to that observed in HAND subjects. The present study was undertaken to discover novel mechanisms of gp120 neurotoxicity that could explain how the envelope protein promotes neurite pruning. Gp120 has been shown to associate with various intracellular organelles as well as microtubules in neurons. We then analyzed lysates of neurons exposed to gp120 with liquid chromatography mass spectrometry for potential protein interactors. We found that one of the proteins interacting with gp120 is tubulin β-3 (TUBB3), a major component of neuronal microtubules. We then tested the hypothesis that gp120 binds to neuronal microtubules. Using surface plasmon resonance we confirmed that gp120 binds with high affinity to neuronal specific TUBB3. We have also identified the binding site of gp120 to TUBB3. We then designed a small peptide (Helix-A) that displaced gp120 from binding to TUBB3. To determine whether this peptide could prevent gp120-mediated neurotoxicity, we crosslinked Helix-A to mesoporous silica nanoparticles (Helix-A nano) to enhance the intracellular delivery of the peptide. We then tested the neuroprotective property of Helix-A nano against three strains of gp120 in rat cortical neurons. Helix-A nano prevented gp120-mediated neurite simplification as well as neuronal loss. These data propose that gp120 binding to TUBB3 could be another mechanism of gp120 neurotoxicity. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: Neuronal activity sculpts brain development by inducing the transcription of genes such as Brain-Derived Neurotrophic Factor (Bdnf) that modulate the function of synapses. Sensory experience is transduced into changes in gene transcription via the activation of calcium signaling pathways downstream of both L-type voltage gated calcium channels (L-VGCCs) and NMDA-type glutamate receptors (NMDARs). These signaling pathways converge on the regulation of transcription factors including Calcium-Response Factor (CaRF). Whereas CaRF is dispensable for the transcriptional induction of Bdnf following the activation of L-VGCCs, here we show that loss of CaRF leads to enhanced NMDAR-dependent transcription of Bdnf as well as Arc. We identify the NMDAR subunit-encoding gene Grin3a as a regulatory target of CaRF, and we show that expression of both Carf and Grin3a is depressed by the elevation of intracellular calcium, linking the function of this transcriptional regulatory pathway to neuronal activity. We find that light-dependent activation of Bdnf and Arc transcription is enhanced in the visual cortex of young CaRF knockout mice, suggesting a role for CaRF-dependent dampening of NMDAR-dependent transcription in the developing brain. Finally, we demonstrate that enhanced Bdnf expression in CaRF-lacking neurons increases inhibitory synapse formation. Taken together these data reveal a novel role for CaRF as an upstream regulator of NMDAR-dependent gene transcription and synapse formation in the developing brain. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: TGF-β signaling through intracellular Smad3 has been implicated in Parkinson's disease (PD) and it fulfills an important role in the neurogenesis and synaptic plasticity that occurs in the adult dentate gyrus (DG). The long-term potentiation (LTP) induced in the DG by high frequency stimulation of the medial perforant pathway (MPP) is abolished in the DG of Smad3 deficient mice but not in the CA1 hippocampal region. Here we show that NMDA- and AMPA-type glutamate receptors do not participate in the inhibition of LTP associated with Smad3 deficiency. Moreover, there is no difference in the hippocampal GAD65 and GAD67 content, suggesting that GABA biosynthesis remains unaffected. Increased conductance and higher action potential firing thresholds were evident in intracellular recordings of granule cells from Smad3 deficient mice. Interestingly, phasic and tonic GABAA receptor (GABAAR)-mediated neurotransmission is enhanced in the DG of Smad3 deficient mice, and LTP induction can be rescued by inhibiting GABAAR with picrotoxin (PCTX). Hence, Smad3 signaling in the DG appears to be necessary to induce LTP by regulating GABAA neurotransmission, suggesting a central role of this intracellular signaling pathway in the hippocampal brain plasticity related to learning and memory. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: The histamine H3 receptor (H3R), abundantly expressed in the central and the peripheral nervous system, has been recognized as a promising target for the treatment of various important CNS diseases including narcolepsy, Alzheimer's disease and attention deficit hyperactivity disorder. The H3R acts via Gi/o-proteins to inhibit adenylate cyclase activity and modulate MAPK activity. However, the underlying molecular mechanisms for H3R mediation of the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) remains to be elucidated. In the present study, using HEK293 cells stably expressing human H3R and mouse primary cortical neurons endogenously expressing mouse H3R, we found that the H3R-mediated activation of ERK1/2 was significantly blocked by both the pertussis toxin and the MEK1/2 inhibitor U0126. Upon stimulation by H3R agonist histamine or imetit, H3R was shown to rapidly induce ERK1/2 phosphorylation via PLC/PKC-, PLDs- and epidermal growth factor receptor (EGFR) transactivation-dependent pathways. Furthermore, it was also indicated that whilst the βγ-subunits play a key role in H3R-activated ERK1/2 phosphorylation, β-arrestins were not required for ERK1/2 activation. In addition, when the cultured mouse cortical neurons were exposed to oxygen and glucose deprivation conditions (OGD), imetit exhibited neuroprotective properties through the H3R. Treatment of cells with the inhibitor UO126 abolished these protective effects. This suggests a possible neuroprotective role of the H3R-mediated ERK1/2 pathway under hypoxia conditions. These observations may provide new insights into the pharmacological effects and the physiological functions modulated by the H3R-mediated activation of ERK1/2. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: Recently, the topic of traumatic brain injury has gained attention in both the scientific community and lay press. Similarly, there have been exciting developments on multiple fronts in the area of neurochemistry specifically related to purine biology that are relevant to both neuroprotection and neurodegeneration. At the 2105 meeting of the National Neurotrauma Society, a session sponsored by the International Society for Neurochemistry featured three experts in the field of purine biology who discussed new developments that are germane to both the pathomechanisms of secondary injury and development of therapies for traumatic brain injury. This included presentations by Drs. Edwin Jackson on the novel 2′,3’ cAMP pathway in neuroprotection, Detlev Boison on adenosine in posttraumatic seizures and epilepsy, and Michael Schwarzschild on the potential of urate to treat central nervous system injury. This mini review summarizes the important findings in these three areas and outlines future directions for the development of new purine-related therapies for traumatic brain injury and other forms of central nervous system injury. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: Histamine, an important modulator of the arousal states of the central nervous system, has been reported to contribute an excitatory drive at the hypoglossal motor nucleus to the genioglossus (GG) muscle, which is involved in the pathogenesis of obstructive sleep apnea (OSA). However, the effect of histamine on hypoglossal motoneurons (HMNs) and the underlying signaling mechanisms has remained elusive. Here, whole-cell patch-clamp recordings were conducted using neonatal rat brain sections, which showed that histamine excited HMNs with an inward current under voltage-clamp and a depolarization membrane potential under current-clamp via histamine H1 receptors (H1Rs). The phospholipase C (PLC) inhibitor U-73122 blocked H1Rs-mediated excitatory effects, but protein kinase A inhibitor and protein kinase C inhibitor did not, indicating that the signal transduction cascades underlying the excitatory action of histamine on HMNs was H1R/Gq/11/PLC/ inositol-1,4,5-trisphosphate (IP3). The effects of histamine were also dependent on extracellular Na+ and intracellular Ca2+, which took place via activation of Na+-Ca2+ exchangers. These results identify the signaling molecules associated with the regulatory effect of histamine on HMNs. The findings of the present study may provide new insights into therapeutic approaches in OSA. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: In this study, we used proton-localized spectroscopy ((1) H-MRS) for the acquisition of the neurochemical profile longitudinally in a novel rat model of human wild type alpha-synuclein (a-syn) overexpression. Our goal was to find out if the increased a-syn load in this model could be linked to changes in metabolites in the frontal cortex. Animals injected with AAV vectors encoding for human a-syn formed the experimental group, whereas green fluorescent protein (GFP) expressing animals were used as the vector-treated control group and a third group of uninjected animals were used as naïve controls. Data was acquired at 2, 4 and 8 month time-points. Nineteen metabolites were quantified in the MR spectra using LCModel software. Based on 92 spectra, we evaluated any potential gender effect and found that Lactate levels were lower in males compared to females, while the opposite was observed for Ascorbate. Next, we assessed the effect of age and found increased levels of GABA, Tau and GPC+PCho. Finally, we analyzed the effect of treatment and found that Lactate levels (p=0.005) were specifically lower in the a-syn group compared to the GFP and control groups. Additionally, Ascorbate levels (p=0.05) were increased in the vector-injected groups, while glucose levels remained unchanged. This study indicates that the metabolic switch between Glucose-Lactate could be detectable in-vivo and might be modulated by Ascorbate. No concomitant changes were found in markers of neuronal integrity (e.g. NAA) consistent with the fact that a-syn overexpression in cortical neurons did not result in neurodegeneration in this model. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: Stress-responsive neuronal membrane glycoprotein M6a (Gpm6a) functions in neurite extension, filopodium and spine formation and synaptogenesis. The mechanisms of Gpm6a action in these processes are incompletely understood. Previously, we identified the actin regulator Coronin-1a (Coro1a) as a putative Gpm6a interacting partner. Here, we used coimmunoprecipitation assays with the anti-Coro1a antibody to show that Coro1a associates with Gpm6a in rat hippocampal neurons. By immunofluorescence microscopy we demonstrated that in hippocampal neurons Coro1a localizes in F-actin enriched regions and some of Coro1a spots colocalize with Gpm6a labeling. Notably, the overexpression of a dominant-negative form of Coro1a as well as its downregulation by siRNA interfered with Gpm6a-induced filopodium formation. Coro1a is known to regulate the plasma membrane translocation and activation of small GTPase Rac1. We show that Coro1a coimmunoprecipitates with Rac1 together with Gpm6a. Pharmacological inhibition of Rac1 resulted in a significant decrease of filopodium formation by Gpm6a. The same was observed upon the coexpression of Gpm6a with the inactive GDP-bound form of Rac1. In this case the elevated membrane recruitment of GDP-bound Rac1was detected as well. Moreover, the kinase activity of the p21-activated kinase 1 (Pak1), a main downstream effector of Rac1 that acts downstream of Coro1a, was required for Gpm6a-induced filopodium formation. Taken together, our results provide evidence that a signaling pathway including Coro1a, Rac1, and Pak1 facilitates Gpm6a-induced filopodium formation. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: Fetal alcohol spectrum disorder (FASD) is the most common cause of mental disabilities in the western world. It has been quite established that acute alcohol exposure can dramatically affect astrocyte function. Because the effects of early alcohol exposure on cell physiology can persist into adulthood, we tested the hypothesis that ethanol exposure in ferrets during a period equivalent to the last months of human gestation leads to persistent changes in astrocyte secretome in vitro. Animals were treated with ethanol (3.5g/kg) or saline between post-natal day (P)10-30. At P31, astrocyte cultures were made and cells were submitted to stable isotope labeling by amino acids (SILAC). 24h-conditioned media of cells obtained from ethanol- or saline-treated animals (ET-CM or SAL-CM) were collected and analyzed by quantitative mass spectrometry in tandem with liquid chromatography. Here we show that 65 out of 280 quantifiable proteins displayed significant differences comparing ET-CM to SAL-CM. Among the 59 proteins that were found to be reduced in ET-CM we observed components of the extracellular matrix such as Laminin subunits α2, α4, β1, β2 and γ1 and the proteoglycans Biglycan, Heparin Sulfate Proteoglycan 2 and Lumican. Proteins with trophic function such as Insulin-Like Growth Factor Binding Protein 4, Pigment Epithelium-Derived Factor and Clusterin as well as proteins involved on modulation of proteolysis such as TIMP-1 and PAI-1 were also reduced. In contrast, pro-synaptogeneic proteins like Thrombospondin-1, Hevin as well as the modulator of extracelular matrix expression, Angiotensinogen, were found increased in ET-CM. The analysis of interactome maps through Ingenuity Pathway Analysis demonstrated that the Amyloid beta A4 protein precursor (APP), which was found reduced in ET-CM, was previously shown to interact with ten other proteins that exhibited significant changes in the ET-CM. Taken together our results strongly suggest that early exposure to teratogens such as alcohol may lead to an enduring change in astrocyte secretome. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: The amyloid precursor protein (APP) and its paralogs, APLP1 and APLP2, are metalloproteins with a putative role both in synaptogenesis and in maintaining synapse structure. Here, we studied the effect of zinc on membrane localization, adhesion and secretase cleavage of APP, APLP1 and APLP2 in cell culture and rat neurons. For this we employed live-cell microscopy techniques, a microcontact printing adhesion assay and ELISA for protein detection in cell culture supernatants. We report that zinc induces the multimerization of proteins of the amyloid precursor protein family and enriches them at cellular adhesion sites. Thus, zinc facilitates the formation of de novo APP and APLP1 containing adhesion complexes, whereas it does not have such influence on APLP2. Furthermore, zinc-binding prevented cleavage of APP and APLPs by extracellular secretases. In conclusion, the complexation of zinc modulates neuronal functions of APP and APLPs by (i) regulating formation of adhesion complexes, most prominently for APLP1, and (ii) by reducing the concentrations of neurotrophic soluble APP/APLP ectodomains. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry
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    ABSTRACT: Accumulation of 2-methylcitric acid (2MCA) is observed in methylmalonic and propionic acidemias, which are clinically characterized by severe neurological symptoms. The exact pathogenetic mechanisms of brain abnormalities in these diseases are poorly established and very little has been reported on the role of 2MCA. In the present work we found that 2MCA markedly inhibited ADP-stimulated and uncoupled respiration in mitochondria supported by glutamate, with a less significant inhibition in pyruvate plus malate-respiring mitochondria. However, no alterations occurred when α-ketoglutarate or succinate was used as respiratory substrates, suggesting a defect on glutamate oxidative metabolism. It was also observed that 2MCA decreased ATP formation in glutamate plus malate or pyruvate plus malate-supported mitochondria. Furthermore, 2MCA inhibited glutamate dehydrogenase (GDH) activity at concentrations as low as 0.5 mM. Kinetic studies revealed that this inhibitory effect was competitive in relation to glutamate. In contrast, assays of osmotic swelling in non-respiring mitochondria suggested that 2MCA did not significantly impair mitochondrial glutamate transport. Finally, 2MCA provoked a significant decrease of mitochondrial membrane potential and induced swelling in Ca(2+) -loaded mitochondria supported by different substrates. These effects were totally prevented by cyclosporine A plus ADP or ruthenium red, indicating induction of mitochondrial permeability transition (PT). Taken together, our data strongly indicate that 2MCA behaves as a potent inhibitor of glutamate oxidation by inhibiting GDH activity and as a PT inducer, disturbing mitochondrial energy homeostasis. We presume that 2MCA-induced mitochondrial deleterious effects may contribute to the pathogenesis of brain damage in patients affected by methylmalonic and propionic acidemias. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of Neurochemistry