Journal of Neurochemistry

Cover image for Vol. 138 Issue 5

Early View (Online Version of Record published before inclusion in an issue)

Edited By: Jörg Schulz

Impact Factor: 3.842

ISI Journal Citation Reports © Ranking: 2015: 71/256 (Neurosciences); 83/289 (Biochemistry & Molecular Biology)

Online ISSN: 1471-4159

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  1. 1 - 71
  1. Short Communication

    1. The oligodendrocyte-specific antibody ‘CC1’ binds Quaking 7

      Jenea M. Bin, Stephanie N. Harris and Timothy E. Kennedy

      Version of Record online: 24 AUG 2016 | DOI: 10.1111/jnc.13745

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      The monoclonal antibody anti-adenomatous polyposis coli (APC) clone CC1, is the antibody most commonly used to specifically label the cell bodies of mature oligodendrocytes. Despite being raised against APC, previous studies showed this antibody binds another unknown antigen. We show that the CC1 antibody binds Quaking (QKI) 7, an RNA-binding protein which is highly up-regulated in myelinating oligodendrocytes.

  2. Original Articles

    1. Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone in SH-SY5Y cells

      Jaishree Jalewa, Mohit Kumar Sharma and Christian Hölscher

      Version of Record online: 24 AUG 2016 | DOI: 10.1111/jnc.13736

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      GLP-1, GIP and dual incretin receptor agonists showed protective effects in SH-SY5Y cells treated with the stressor Rotenone. The novel GLP-1/GIP dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. The drugs protected the cells from rotenone-induced impairment in cell growth and Akt activation, mitochondrial damage, impairments of autophagy and apoptotic cell signalling. See paper for details.

  3. Reviews

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      Mitochondrial dysfunction in Parkinson's disease

      Anindita Bose and M. Flint Beal

      Version of Record online: 21 AUG 2016 | DOI: 10.1111/jnc.13731

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      Bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations, alterations in mitochondrial dynamics, alterations in trafficking/transport and mitochondrial movement, abnormal size and morphology, impairment of transcription and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we focus on the mechanisms underlying mitochondrial dysfunction in PD and bring to the forefront new signaling pathways that may be involved in PD. We also provide an overview of therapeutic strategies to improve mitochondrial defects in PD.

      This article is part of a special issue on Parkinson disease.

  4. Original Articles

    1. Proteolysis of α-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology

      Amanda N. Sacino, Mieu M. Brooks, Paramita Chakrabarty, Kaustuv Saha, Habibeh Khoshbouei, Todd E. Golde and Benoit I. Giasson

      Version of Record online: 19 AUG 2016 | DOI: 10.1111/jnc.13743

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      α-synuclein (αS) cytoplasmic inclusions can present in a spectrum of neurodegenerative disorders. Exogenous αS fibrils efficiently attach to the plasma membrane. They can subsequently internalize and are degraded within the endosomal/lysosomal system. However, internalized αS amyloid fibrils may also overwhelm the endosomal/lysosomal machinery leading to the induction of cytoplasmic inclusions comprised of endogenous αS.

    2. Time-dependent uptake and trafficking of vesicles capturing extracellular S100B in cultured rat astrocytes

      Eva Lasič, Fabiana Galland, Nina Vardjan, Jernej Šribar, Igor Križaj, Marina Concli Leite, Robert Zorec and Matjaž Stenovec

      Version of Record online: 19 AUG 2016 | DOI: 10.1111/jnc.13754

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      This study reveals the vesicular clearance mechanism of extracellular S100B in astrocytes. Initially, fluorescent S100B internalizes into smaller endocytotic vesicles than dextran molecules. At a later stage, both probes co-localize within endolysosomes. S100B internalization is both dynamin- and RAGE-dependent, whereas dextran internalization is dependent on dynamin. Vesicle internalization likely mitigates the toxic effects of extracellular S100B and other waste products.

    3. Genotype differences in anxiety and fear learning and memory of WT and ApoE4 mice associated with enhanced generation of hippocampal reactive oxygen species

      Laura E. Villasana, Sydney Weber, Tunde Akinyeke and Jacob Raber

      Version of Record online: 19 AUG 2016 | DOI: 10.1111/jnc.13737

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      Mice with apolipoprotein E4 (E4), a risk factor for Alzheimer's disease, have greater anxiety-like and conditioned fear behaviors than wild-type (WT) mice. Generation of reactive oxygen species (ROS, in red) 3 months following 56Fe irradiation, a component of the space environment astronauts are exposed to, is more pronounced in the hippocampus of E4 than WT mice. In E4, but not WT, mice, hippocampal levels of the oxidative stress-relevant marker heme oxygenase-1 are higher in irradiated than sham-irradiated E4 mice.

  5. Reviews

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      Reflections on 60 years of publication of the Journal of Neurochemistry

      Anthony J. Turner, Natalia N. Nalivaeva, Frode Fonnum, Keith F. Tipton, Laura Hausmann and Jörg B. Schulz

      Version of Record online: 17 AUG 2016 | DOI: 10.1111/jnc.13673

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      This article celebrates 60 years of publication of Journal of Neurochemistry including personal reminiscences from some of the Chief Editors, past and present, as well as input from some of the key contributors to the Journal over this period. We highlight the scientific, technological, and publishing developments along the way, with reference to key papers published in the Journal. The support of the Journal toward the aims and objectives of the International Society for Neurochemistry (ISN) is also emphasized.

      This article is part of the 60th Anniversary special issue.

    2. You have free access to this content
      A Learned Society's Perspective on Publishing

      Kunihiko Suzuki, Alan Edelson, Leslie L. Iversen, Laura Hausmann, Jörg B. Schulz and Anthony J. Turner

      Version of Record online: 17 AUG 2016 | DOI: 10.1111/jnc.13674

      Scientific journals that are owned by a learned society, like the Journal of Neurochemistry (JNC) which is owned by the International Society for Neurochemistry (ISN), benefit the scientific community in that a large proportion of the income is returned to support the scientific mission of the Society. The income generated by the JNC enables the ISN to organize conferences as a platform for members and non-members alike to share their research, supporting researchers particularly in developing countries by travel grants and other funds, and to promote education in student schools. These direct benefits and initiatives for ISN members and non-members distinguish a society journal from pure commerce. However, the world of scholarly publishing is changing rapidly. Open access models have challenged the business model of traditional journal subscription and hence provide free access to publicly funded scientific research. In these models, the manuscript authors pay a publication cost after peer review and acceptance of the manuscript. Over the last decade, numerous new open access journals have been launched and traditional subscription journals have started to offer open access (hybrid journals). However, open access journals pertain to the general scheme that, of all participating parties, the publisher receives the highest financial benefit. The income is generated by researchers whose positions and research are mostly financed by tax payers’ or funders’ money, reviewers and editors, who frequently are not reimbursed. Last but not least, the authors pay for the publication of their work after a rigorous and sometimes painful review process. JNC itself has an open access option, at a significantly reduced cost for Society members as an additional benefit. This article provides first-hand insights from a long-standing Editor-in-Chief, Kunihiko Suzuki, about the history of JNC's ownership and about difficulties and battles fought on the way to its current success and reputation today.

      This article is part of the 60th Anniversary special issue.

    3. You have free access to this content
      How does adenosine control neuronal dysfunction and neurodegeneration?

      Rodrigo A. Cunha

      Version of Record online: 16 AUG 2016 | DOI: 10.1111/jnc.13724

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      The main physiological role of the adenosine modulation system is to sharp the salience of information encoding through a combined action of adenosine A2A receptors (A2AR) in the synapse undergoing an alteration of synaptic efficiency with an increased inhibitory action of A1R in all surrounding synapses. Brain insults trigger an up-regulation of A2AR in an attempt to bolster adaptive plasticity together with adenosine release and A1R desensitization; this favors synaptotocity (increased A2AR) and decreases the hurdle to undergo degeneration (decreased A1R). Maximal neuroprotection is expected to result from a combined A2AR blockade and increased A1R activation.

      This article is part of a mini review series:“Synaptic Function and Dysfunction in Brain Diseases”.

  6. Original Articles

    1. You have full text access to this OnlineOpen article
      Functional interaction between Lypd6 and nicotinic acetylcholine receptors

      Maria Arvaniti, Majbrit M. Jensen, Neeraj Soni, Hong Wang, Anders B. Klein, Nathalie Thiriet, Lars H. Pinborg, Pretal P. Muldoon, Jacob Wienecke, M. Imad Damaj, Kristi A. Kohlmeier, Marjorie C. Gondré-Lewis, Jens D. Mikkelsen and Morten S. Thomsen

      Version of Record online: 15 AUG 2016 | DOI: 10.1111/jnc.13718

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      Regulatory proteins of the Lynx family modulate the function of nicotinic receptors (nAChRs). We report for the first time that the Lynx protein Lypd6 binds to nAChRs in human brain extracts, and that recombinant Lypd6 decreases nicotine-induced ERK phosphorylation and attenuates nicotine-induced hippocampal inward currents. Our findings suggest that Lypd6 is a versatile inhibitor of cholinergic signaling in the brain.

    2. Novel molecular insights into the critical role of sulfatide in myelin maintenance/function

      Juan Pablo Palavicini, Chunyan Wang, Linyuan Chen, Sareen Ahmar, Juan Diego Higuera, Jeffrey L. Dupree and Xianlin Han

      Version of Record online: 15 AUG 2016 | DOI: 10.1111/jnc.13738

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      Cerebroside sulfotransferase (CST) catalyzes the production of sulfatide, a major class of myelin-specific lipids. CST knockout (CST−/−) mice in which sulfatide is completely depleted are born healthy, but display myelin abnormalities We show in our study that sulfatide depletion leads to losses of myelin proteins and lipids, and impairment of myelin functions, unraveling novel molecular insights into the critical role of sulfatide in myelin maintenance/function.

    3. Dopamine D3 autoreceptor inhibition enhances cocaine potency at the dopamine transporter

      Molly M. McGinnis, Cody A. Siciliano and Sara R. Jones

      Version of Record online: 15 AUG 2016 | DOI: 10.1111/jnc.13732

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      We propose a model whereby presynaptic dopamine autoreceptors dynamically modulate cocaine potency through two separate mechanisms. We demonstrate that D2 agonists decrease cocaine potency, whereas D3 antagonists increase cocaine potency, likely through an allosteric mechanism outside of their canonical actions on dopamine release. These findings give important and novel insight into the contribution of D2/D3 autoreceptors to dopamine transporter function.

    4. Role of purinergic P2X4 receptors in regulating striatal dopamine homeostasis and dependent behaviors

      Sheraz Khoja, Vivek Shah, Damaris Garcia, Liana Asatryan, Michael W. Jakowec and Daryl L. Davies

      Version of Record online: 15 AUG 2016 | DOI: 10.1111/jnc.13734

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      We propose that P2X4 receptors (P2X4Rs) regulate dopamine (DA) homeostasis and associated behaviors. Pre-synaptic and post-synaptic DA markers were significantly altered in the dorsal and ventral striatum of P2X4R KO mice, implicating altered DA neurotransmission. Sensorimotor gating deficits in P2X4R KO mice were rescued by DA antagonists. Ivermectin (IVM), a positive modulator of P2X4Rs, enhanced levodopa (L-DOPA)-induced motor behavior. These studies highlight potential interactions between P2X4Rs and DA system.

    5. The intermediate filament protein vimentin is essential for axonotrophic effects of Clostridium botulinum C3 exoenzyme

      Andrej Adolf, George Leondaritis, Astrid Rohrbeck, Britta Johanna Eickholt, Ingo Just, Gudrun Ahnert-Hilger and Markus Höltje

      Version of Record online: 9 AUG 2016 | DOI: 10.1111/jnc.13739

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      Primary neuronal cultures from vimentin knockout (KO) mice were used to study the impact of vimentin on axonal growth and internalization of C3bot. In contrast to wild type, vimentin knockout neurons were insensitive to the axonotrophic effects of C3bot. Application of extracellular vimentin (recombinant vimentin) to vimentin KO neurons completely restored the growth-promoting effects of C3bot. In line with this uptake of C3bot into vimentin KO neurons was strongly decreased resulting in reduced ADP-ribosylation of RhoA and B as detected by an antibody recognizing selectively ADP-ribosylated RhoA/B.

    6. Glycine release from astrocytes via functional reversal of GlyT1

      Koji Shibasaki, Nobutake Hosoi, Ryosuke Kaneko, Makoto Tominaga and Katsuya Yamada

      Version of Record online: 9 AUG 2016 | DOI: 10.1111/jnc.13741

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      We combined two different methods to confirm the glycine (Gly) release from astrocytes. Firstly, we analyzed the supernatant of astrocytes by amino acid analyzer after DA stimulation, and detect significant glycine peak. Furthermore, we utilized a patch-clamp biosensor method to confirm the glycine release from astrocytes by using GlyRα1 and Glyβ-expressing HEK293T cells, and detected significant glycine-evoked current upon DA stimulation. We clearly demonstrated that DA induces glycine release from astrocytes through D5R-Gq-PLC pathways. Surprisingly, DA caused a functional reversal of GlyT1, an astrocytic type of glycine transporter, causing astrocytes to release glycine.

    7. An approach to comprehensive genome and proteome expression analyses in Schwann cells and neurons during peripheral nerve myelin formation

      Salla M. Kangas, Steffen Ohlmeier, Raija Sormunen, Eeva-Mari Jouhilahti, Sirkku Peltonen, Juha Peltonen and Anthony M. Heape

      Version of Record online: 4 AUG 2016 | DOI: 10.1111/jnc.13722

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      We have developed a reproducible and robust cell culture-based approach, accompanied by a genome-wide expression data set, which allows studying myelination in the peripheral nervous system at the proteomic and transcriptomic levels in Schwann cells and neurons. Myelinating dorsal root explant cultures, prepared from C57BL/6J mouse embryos, present distinct developmental stages comparable to those observed in a peripheral nerve in situ. This model can be used for identifying the protein functional networks and modules related to peripheral nerve myelin formation.

    8. Different roles of the small GTPases Rac1, Cdc42, and RhoG in CALEB/NGC-induced dendritic tree complexity

      Jana Schulz, Kristin Franke, Manfred Frick and Stefan Schumacher

      Version of Record online: 4 AUG 2016 | DOI: 10.1111/jnc.13735

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      Rho GTPases play a prominent role in dendritic branching. CALEB/NGC is a transmembrane member of the epidermal growth factor (EGF) family that mediates dendritic branching, dependent on Rac1. CALEB/NGC stimulates Rac1 activity. RhoG inhibits CALEB/NGC-mediated dendritic branching by decreasing the amount of CALEB/NGC at the plasma membrane. Palmitoylated, but not prenylated form of the GTPase Cdc42 decreases dendritic branching. CALEB/NGC and Cdc42 are not directly interconnected in regulating dendritic branching. Thus, CALEB/NGC organizes a Rho GTPase signaling module at the plasma membrane for shaping dendritic trees.

    9. Cell death caused by the synergistic effects of zinc and dopamine is mediated by a stress sensor gene Gadd45b – implication in the pathogenesis of Parkinson's disease

      Tien-Chun Yang, Pei-Chun Wu, I-Fang Chung, Jhih-Hang Jiang, Ming-Ji Fann and Lung-Sen Kao

      Version of Record online: 4 AUG 2016 | DOI: 10.1111/jnc.13728

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      Zinc and dopamine are implicated in the degeneration of dopaminergic neurons. We previously demonstrated that zinc and dopamine induced synergistic effects on PC12 cell death. Results from this study show that these synergistic effects can be accounted for by activation of the Gadd45b-induced cell death pathway and inhibition of the p38/JNK survival pathway. We provide in vitro and in vivo evidence to support a novel role for Gadd45b in the pathogenesis of Parkinson's disease.

  7. Reviews

    1. You have full text access to this OnlineOpen article
      Perturbed proteostasis in autism spectrum disorders

      Susana R. Louros and Emily K. Osterweil

      Version of Record online: 4 AUG 2016 | DOI: 10.1111/jnc.13723

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      Dynamic changes in synaptic strength rely on de novo protein synthesis and protein degradation by the ubiquitin proteasome system (UPS). Disruption of either of these cellular processes will result in significant impairments in synaptic plasticity and memory formation. Mutations in several genes encoding regulators of mRNA translation (i.e. FMR1) and protein degradation (i.e. UBE3A) have been associated with an increased risk for autism spectrum disorders and intellectual disability (ASD/ID). These mutations similarly disrupt protein homeostasis (proteostasis). Compensatory changes that reset the rate of proteostasis may contribute to the neurological symptoms of ASD/ID. This review summarizes recent work investigating the role of the UPS in synaptic plasticity at glutamatergic synapses, and proposes that dysfunctional proteostasis is a common consequence of several genetic mutations linked to ASD.

      This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.

  8. Original Articles

    1. Subanesthetic doses of ketamine stabilize the fusion pore in a narrow flickering state in astrocytes

      Eva Lasič, Boštjan Rituper, Jernej Jorgačevski, Marko Kreft, Matjaž Stenovec and Robert Zorec

      Version of Record online: 4 AUG 2016 | DOI: 10.1111/jnc.13715

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      This study demonstrates a novel effect of ketamine on the fusion pore. High-resolution cell-attached membrane capacitance measurements revealed that ketamine evokes long-lasting flickering of a narrow fusion pore that is incapable of transiting to full fission. Astrocytic vesicle fusion/retrieval modified by subanesthetic ketamine doses most likely affects gliotransmission and indicates a non-neuronal mechanism of ketamine action that may contribute to its behavioral effects.

  9. Reviews

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      Fas apoptosis inhibitory molecules: more than death-receptor antagonists in the nervous system

      Laura Planells-Ferrer, Jorge Urresti, Elena Coccia, Koen M. O. Galenkamp, Isabel Calleja-Yagüe, Joaquín López-Soriano, Paulina Carriba, Bruna Barneda-Zahonero, Miguel F. Segura and Joan X. Comella

      Version of Record online: 3 AUG 2016 | DOI: 10.1111/jnc.13729

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      Even though they share name and inhibit Fas-induced cell death, Fas apoptotic inhibitory molecules (FAIMs) are not structurally related and inhibit apoptosis through completely different mechanisms. In this review, we describe FAIM1, FAIM2, and FAIM3 functions in the nervous system, and their implication in diverse pathologies such as neurodegenerative disease, cancer, or autoimmune diseases.

  10. Original Articles

    1. Reduced sterol regulatory element-binding protein (SREBP) processing through site-1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro

      Hubert Monnerie, Micah Romer, Brigid K. Jensen, John S. Millar, Kelly L. Jordan-Sciutto, Sangwon F. Kim and Judith B. Grinspan

      Version of Record online: 2 AUG 2016 | DOI: 10.1111/jnc.13721

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      The role of sterol regulatory element-binding proteins (SREBPs), transcription factors regulating lipid synthesis, was investigated during oligodendrocyte differentiation in vitro. Blocking site-1 protease-induced cleavage of SREBP inhibited oligodendrocyte process growth and myelin basic protein expression, reduced expression of genes involved in lipid synthetic pathways and de novo cholesterol synthesis. This suggests SREBPs activity during oligodendrocyte maturation is required for myelin formation and integrity.

    2. Discovery of a fluorinated 4-oxo-quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2

      Roger Slavik, Adrienne Müller Herde, Ahmed Haider, Stefanie D. Krämer, Markus Weber, Roger Schibli, Simon M. Ametamey and Linjing Mu

      Version of Record online: 2 AUG 2016 | DOI: 10.1111/jnc.13716

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      Cannabinoid receptor type 2 (CB2) is an interesting target for PET imaging. Specific binding of [18F]RS-126 in CB2-positive spleen tissue (white arrow head) was confirmed in in vivo displacement experiments with rats. Time activity curve of [18F]RS-126 in the spleen after the addition of GW405833 (CB2 specific ligand, green) demonstrates faster radiotracer elimination (blue) compared to the tracer only (red).

    3. Nucleolin inhibitor GroA triggers reduction in epidermal growth factor receptor activation: Pharmacological implication for glial scarring after spinal cord injury

      Yona Goldshmit, Sari Schokoroy Trangle, Fabian Afergan, Tal Iram and Ronit Pinkas-Kramarski

      Version of Record online: 1 AUG 2016 | DOI: 10.1111/jnc.13730

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      A major barrier for axonal regeneration after spinal cord injury is glial scar created by reactive and proliferating astrocytes. EGFR mediate astrocyte reactivity. We showed that inhibition of nucleolin by GroA, reduces EGFR activation, which results in attenuation of astrocyte reactivity and proliferation in vivo and in vitro. EGFR, epidermal growth factor receptor.

    4. Traumatic brain injury decreases AMP-activated protein kinase activity and pharmacological enhancement of its activity improves cognitive outcome

      Julia L. Hill, Nobuhide Kobori, Jing Zhao, Natalia S. Rozas, Michael J. Hylin, Anthony N. Moore and Pramod K. Dash

      Version of Record online: 1 AUG 2016 | DOI: 10.1111/jnc.13726

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      Increased phosphorylation of Thr172 activates AMP-activated protein kinase (AMPK) under conditions of low cellular energy availability. This leads to inhibition of energy consuming, while activating energy generating, processes. Hill et al., present data to indicate that TBI decreases Thr172 phosphorylation and that its stimulation by pharmacological agents offers neuroprotection and improves memory. These results suggest that decreased AMPK phosphorylation after TBI incorrectly signals the injured brain that excess energy is available, thereby contributing to the cellular energy crisis and memory impairments.

  11. Reviews

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      Puzzling out presynaptic differentiation

      Maria J. Pinto and Ramiro D. Almeida

      Version of Record online: 28 JUL 2016 | DOI: 10.1111/jnc.13702

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      We provide a detailed description of the mechanisms leading to the formation of new presynaptic terminals. In brief, soma-derived packets of pre-assembled material are trafficked to distant axonal sites. Synaptogenic factors from dendritic or glial provenance activate downstream intra-axonal mediators to trigger clustering of passing material and their correct organization into a new presynaptic bouton.

      This article is part of a mini review series:“Synaptic Function and Dysfunction in Brain Diseases”.

  12. Original Articles

    1. LAP proteins are localized at the post-synaptic membrane of neuromuscular junctions and appear to modulate synaptic morphology and transmission

      Bojana Kravic, Danyil Huraskin, Alexander D. Frick, Jasmin Jung, Veronika Redai, Ralf Palmisano, Sylvie Marchetto, Jean-Paul Borg, Lin Mei and Said Hashemolhosseini

      Version of Record online: 28 JUL 2016 | DOI: 10.1111/jnc.13710

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      LAP proteins [leucine-rich repeats (LRRs) and PDZ domain] Erbin, Lano, and Scribble are expressed by different entities at neuromuscular junctions of mice. Erbin is expressed by myelinating Schwann cells, Erbin and Lano by terminal Schwann cells, Lano and Scribble by motor neurons, and all three by the muscle fiber. Moreover, Erbin, Lano, and Scribble are involved in proper aggregation of neurotransmitter receptors (AChRs) at NMJs.

    2. Loss of divalent metal transporter 1 function promotes brain copper accumulation and increases impulsivity

      Murui Han, JuOae Chang and Jonghan Kim

      Version of Record online: 22 JUL 2016 | DOI: 10.1111/jnc.13717

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      Iron-copper model: Mutations in the divalent metal transporter 1 (DMT1) decrease body iron status and up-regulate copper absorption, which leads to copper loading in the brain and consequently increases metal-induced oxidative stress. This event disrupts GABAergic neurotransmission and promotes impulsivity-like behavior. Our model provides better understanding of physiological risks associated with imbalanced metal metabolism in mental function and, more specifically, the interactions with GABA and redox control in the treatment of emotional disorders.

    3. Haptoglobin increases the vulnerability of CD163-expressing neurons to hemoglobin

      Jing Chen-Roetling and Raymond F. Regan

      Version of Record online: 22 JUL 2016 | DOI: 10.1111/jnc.13720

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      Haptoglobin (Hp) binds hemoglobin (Hb) with high affinity and provides the primary defense against its toxicity after intravascular hemolysis. Neurons are exposed to extracellular Hb after CNS hemorrhage, and a therapeutic effect of Hp via Hb sequestration has been hypothesized. In this study, we tested the hypothesis that Hp protects neurons from Hb in primary mixed cortical cell cultures. Binding of hemoglobin to haptoglobin directs Hb to CD163 +  neurons and microglia and away from astrocytes. This decreases expression of ferritin by astrocytes and increases neuronal injury.

    4. Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis

      Hieu Minh Ta, Thuong Manh Le, Hiroshi Ishii, Mika Takarada-Iemata, Tsuyoshi Hattori, Koji Hashida, Yasuhiko Yamamoto, Kazutoshi Mori, Ryosuke Takahashi, Yasuko Kitao and Osamu Hori

      Version of Record online: 18 JUL 2016 | DOI: 10.1111/jnc.13714

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      We investigated the relevance of ATF6α, an upstream regulator of part of the UPR, in EAE. Deletion of Atf6α suppressed inflammation, and ameliorated demyelination after EAE. Bone marrow transfer experiments and adoptive transfer of autoimmune CD4+ T cells revealed that CNS-resident cells are responsible for the phenotypes in Atf6α−/− mice. Furthermore, inflammatory response was reduced in Atf6α−/− microglia, and was associated with degradation of NF-κB p65. Our results demonstrate a novel role for ATF6α in microglia-mediated inflammation.

    5. Activity and circadian rhythm influence synaptic Shank3 protein levels in mice

      Tasnuva Sarowar, Resham Chhabra, Antonietta Vilella, Tobias M. Boeckers, Michele Zoli and Andreas M. Grabrucker

      Version of Record online: 15 JUL 2016 | DOI: 10.1111/jnc.13709

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      Using wild-type CBA mice, we show that Shank3 is a highly dynamic and activity-regulated protein at synapses. In the hippocampus, changes in synaptic Shank3 levels are influenced by circadian rhythm/melatonin concentration, while running activity increases and decreases levels of Shank3 in the cortex and striatum respectively.

    6. Beneficial roles of melanoma cell adhesion molecule in spinal cord transection recovery in adult zebrafish

      Chun-Jie Liu, Lin Xie, Chun Cui, Min Chu, Hou-De Zhao, Li Yao, Yu-Hong Li, Melitta Schachner and Yan-Qin Shen

      Version of Record online: 12 JUL 2016 | DOI: 10.1111/jnc.13707

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      In the context of adult zebrafish spinal cord injury, we proved that Melanoma cell adhesion molecule (MCAM) is beneficial to the recovery, possibly via mechanisms of angiogenensis and inflammation. MCAM promotes angiogenesis by adjusting VEGFR-2, p-p38 and p-AKT. MCAM affects inflammatory factors such as TNF-α, IL-1β and IL-8. Our results extend the beneficial role of MCAM in the regeneration of central nervous system.

  13. Reviews

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      The clinical symptoms of Parkinson's disease

      Sigurlaug Sveinbjornsdottir

      Version of Record online: 11 JUL 2016 | DOI: 10.1111/jnc.13691

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      Parkinson's disease is a slowly progressing neurodegenerative disorder, causing impaired motor function with slow movements, tremor and gait and balance disturbances. A variety of non-motor symptoms are common in Parkinson's disease. They include disturbed autonomic function with orthostatic hypotension, constipation and urinary disturbances, a variety of sleep disorders and a spectrum of neuropsychiatric symptoms. This article describes the different clinical symptoms that may occur and the clinical course of the disease.

      This article is part of a special issue on Parkinson disease.

    2. You have free access to this content
      Molecular changes in the postmortem parkinsonian brain

      Damien Toulorge, Anthony H. V. Schapira and Rodolphe Hajj

      Version of Record online: 5 JUL 2016 | DOI: 10.1111/jnc.13696

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      Parkinson's is accompanied by multiple changes in the brain that are responsible for the progression of the disease. We describe here the molecular alterations occurring in postmortem brains and classify them as: Neurotransmitters and neurotrophic factors; Lewy bodies and Parkinson's-linked genes; Transition metals, calcium and calcium-binding proteins; Inflammation; Mitochondrial abnormalities and oxidative stress; Abnormal protein removal and degradation; Apoptosis and transduction pathways.

      This article is part of a special issue on Parkinson disease.

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      Mechanisms of homeostatic plasticity in the excitatory synapse

      Dominique Fernandes and Ana Luísa Carvalho

      Version of Record online: 1 JUL 2016 | DOI: 10.1111/jnc.13687

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      Hebbian forms of synaptic plasticity, such as long-term potentiation (LTP), induce long-lasting changes in synaptic strength, which can be destabilizing and drive activity to saturation. Conversely, homeostatic plasticity operates to compensate for prolonged activity changes, stabilizing neuronal firing within a dynamic physiological range. We review mechanisms underlying homeostatic plasticity, and address how neurons integrate distinct forms of plasticity for proper brain function.

    4. You have full text access to this OnlineOpen article
      Diversity matters – heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease

      Daniela Maria Vogt Weisenhorn, Florian Giesert and Wolfgang Wurst

      Version of Record online: 27 JUN 2016 | DOI: 10.1111/jnc.13670

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      Several decades of research revealed that the neurons in the ventral mesencephalic dopaminergic complex do not form a homogeneous group in respect to anatomy, physiology, function, molecular identity or vulnerability/dysfunction in diseases like Parkinson's disease (PD). Here, we review how this concept evolved and was refined over time and how it shaped our understanding of the pathogenesis of PD. Source of the midbrain image: www.wikimd.org/wiki/index.php/The_Midbrain_or_Mesencephalon; downloaded 28.01.2016. See also Figures and of the paper.

      This article is part of a special issue on Parkinson disease.

    5. You have free access to this content
      Interplay of enzymatic and structural functions of CaMKII in long-term potentiation

      Karam Kim, Takeo Saneyoshi, Tomohisa Hosokawa, Kenichi Okamoto and Yasunori Hayashi

      Version of Record online: 27 JUN 2016 | DOI: 10.1111/jnc.13672

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      Because of its extraordinary abundance within neuronal cells, calmodulin kinase CaMKII has been believed to act as a structural protein as well as an enzyme during synaptic plasticity. In this review, we summarized studies in CaMKII field and provide an insight into how enzymatic and structural functions of CaMKII cooperate with each other for long-term potentiation (LTP) in neurons.

  14. Original Articles

    1. Novel analogs of allopregnanolone show improved efficiency and specificity in neuroprotection and stimulation of proliferation

      Mona Karout, Michel Miesch, Philippe Geoffroy, Stephanie Kraft, Hans-Dieter Hofmann, Ayikoe Guy Mensah-Nyagan and Matthias Kirsch

      Version of Record online: 24 JUN 2016 | DOI: 10.1111/jnc.13693

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      Neurosteroids synthesized in the nervous system are neuroprotective, anti-apoptotic and promote cell proliferation. Such diverse biological actions may result in unwanted side effects, e.g., when neurosteroids would be used for treating neuropathic pain following cytostatic treatment. We have synthesized and tested analogs of the endogenous neurosteroid allopregnanolone selectively stimulating proliferation of neural stem/progenitor cells or exerting neuroprotective effects against amyloid-β toxicity.

    2. The astrocytic response to the dopaminergic denervation of the striatum

      Ingrid Morales, Alberto Sanchez, Clara Rodriguez-Sabate and Manuel Rodriguez

      Version of Record online: 18 JUN 2016 | DOI: 10.1111/jnc.13684

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      The dopaminergic denervation of the striatum induced a severe astrogliosis with a specific profile which included some (e.g. up-regulation of GFAP, GS, S100β, NDRG2, vimentin) but not all (e.g. astrocytic proliferation or differentiation from NG2 cells, astrocytic scars, microgliosis) the characteristics observed after the non-selective striatal lesions. This response may help to understand the role of striatal astrocytes during the dopaminergic denervation which characterizes the first stages of PD.

  15. Reviews

    1. You have free access to this content
      DNA methylation in Parkinson's disease

      Ullrich Wüllner, Oliver Kaut, Laura deBoni, Dominik Piston and Ina Schmitt

      Version of Record online: 10 JUN 2016 | DOI: 10.1111/jnc.13646

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      Parkinson's disease (PD) is conceptualized as a consequence of genetic variants and environment–gene interactions on a background of age-related changes. Epigenetic modifications have been implicated in aging and can be altered by environment stimuli. The review explores the possibility of an epigenetic component in PD, focusing on DNA methylation. Methylation of α-synuclein (SNCA) and microtubule-associated protein tau gene appear to be of particular importance and epigenome-wide methylation studies point to several additional candidate genes which may contribute to the individual susceptibility toward PD.

      This article is part of the special issue on Parkinson disease.

    2. You have free access to this content
      Deep brain stimulation mechanisms: the control of network activity via neurochemistry modulation

      Cameron C. McIntyre and Ross W. Anderson

      Version of Record online: 8 JUN 2016 | DOI: 10.1111/jnc.13649

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      Deep brain stimulation is an effective clinical technology, but detailed therapeutic mechanisms remain undefined. This review provides an overview of the leading hypotheses, which focus on stimulation-induced disruption of network oscillations and integrates possible roles for non-neuronal tissue in explaining the clinical response to therapeutic stimulation.

      This article is part of a special issue on Parkinson disease.

  16. Bench to Bedside

    1. You have free access to this content
      The amyloid cascade hypothesis: are we poised for success or failure?

      Eric Karran and Bart De Strooper

      Version of Record online: 3 JUN 2016 | DOI: 10.1111/jnc.13632

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      We review the amyloid cascade hypothesis (ACH) and compare it with other hypotheses that have been posited to explain the initiation and progression Alzheimer's disease. We document the data that support the ACH, and also reflect upon its deficiencies. We list the recent clinical failures of amyloidocentric drugs and anticipate the results that new therapeutic approaches may deliver.

      This article is part of the 60th Anniversary special issue.

  17. Reviews

    1. You have free access to this content
      The mitochondrial kinase PINK1: functions beyond mitophagy

      Aaron Voigt, Lena A. Berlemann and Konstanze F. Winklhofer

      Version of Record online: 2 JUN 2016 | DOI: 10.1111/jnc.13655

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      Mutations in the PINK1 gene, encoding a mitochondrial kinase, are associated with autosomal recessive Parkinson's disease. In this review, we summarize and discuss the functional roles of PINK1 in maintaining mitochondrial integrity, eliminating damaged mitochondria, and promoting cell survival.

      This article is part of a special issue on Parkinson disease.

  18. Original Articles

    1. Argon mediates protection by interleukin-8 suppression via a TLR2/TLR4/STAT3/NF-κB pathway in a model of apoptosis in neuroblastoma cells in vitro and following ischemia-reperfusion injury in rat retina in vivo

      Felix Ulbrich, Teresa Lerach, Julia Biermann, Kai B. Kaufmann, Wolf A. Lagreze, Hartmut Buerkle, Torsten Loop and Ulrich Goebel

      Version of Record online: 30 MAY 2016 | DOI: 10.1111/jnc.13662

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      Argon exerts its protective effects in vitro and in vivo via toll-like receptors TLR2 and TLR4 signaling, followed by alteration of downstream enzymes. In conclusion, argon mediates its beneficial effects by suppression of STAT3 and NF-κB phosphorylation and subsequent suppression of interleukin IL-8 protein expression. These novel findings may open up opportunities for argon as a therapeutic agent, particularly in the treatment of neuronal injury.

  19. Reviews

    1. You have free access to this content
      How can rAAV-α-synuclein and the fibril α-synuclein models advance our understanding of Parkinson's disease?

      Laura A. Volpicelli-Daley, Deniz Kirik, Lindsay E. Stoyka, David G. Standaert and Ashley S. Harms

      Version of Record online: 4 MAY 2016 | DOI: 10.1111/jnc.13627

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      This review describes two α-synuclein-based rodent models of Parkinson's disease: the rAAV-α-synuclein model and the α-synuclein fibril model. The key features of these models are described, and the extent to which they recapitulate features of PD, such as α-synuclein inclusion formation, loss of dopaminergic synapses in the striatum, motor defects, inflammation, and dopamine neuron death.

      This article is part of a special issue on Parkinson disease.

  20. Past to Future

    1. Synaptic signalling and its interface with neuropathologies: snapshots from the past, present and future

      Philip M. Beart

      Version of Record online: 4 MAY 2016 | DOI: 10.1111/jnc.13598

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      Highlighted are important advances in synaptic signalling over the last decade in the Journal of Neurochemistry. Across all transmitter systems elucidation of circuit function, and notably molecular insights, have underpinned remarkable growth in the identification of targets likely to provide therapeutic benefit in neuropathologies. Another commonality was wide interest in forebrain circuitry and its tonic excitatory control. Increasingly observations relate to signalling in disease and behavioural conditions.

      This article is part of the 60th Anniversary special issue.

    2. Neuroinflammation: the devil is in the details

      Damon J. DiSabato, Ning Quan and Jonathan P. Godbout

      Version of Record online: 4 MAY 2016 | DOI: 10.1111/jnc.13607

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      In this review, we will use brain and spinal cord injury, stress, aging, and other inflammatory events to illustrate the potential harm and benefits inherent to neuroinflammation. Context, course, and duration of the inflammation are highly important to the interpretation of these events, and we aim to provide insight into this by detailing several commonly studied insults.

      This article is part of the 60th anniversary supplemental issue.

  21. Bench to Bedside

    1. Overcoming translational barriers impeding development of Alzheimer's disease modifying therapies

      Todd E. Golde

      Version of Record online: 4 MAY 2016 | DOI: 10.1111/jnc.13583

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      Seminal discoveries made over the past 25 years have provided firm rationale for a new generation of Alzheimer's disease (AD) therapies designed as disease modifying agents that would slow or even reverse the disease course. Unfortunately, no therapy has yet to show significant clinical disease modification. In this review, I describe 10 translational barriers to successful AD disease modification, highlight current efforts addressing some of these barriers, and discuss how the field could focus future efforts to overcome these barriers.

      This article is part of the 60th Anniversary special issue.

    2. Hippocampal metabotropic glutamate receptor long-term depression in health and disease: focus on mitogen-activated protein kinase pathways

      Thomas M. Sanderson, Ellen L. Hogg, Graham L. Collingridge and Sonia A. L. Corrêa

      Version of Record online: 4 MAY 2016 | DOI: 10.1111/jnc.13592

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      mGluR-LTD is a form of synaptic plasticity that impacts on memory formation. In the hippocampus mitogen-activated protein kinases (MAPKs) have been found to be important in mGluR-LTD. In this 60th anniversary special issue article, we review the independent and complementary roles of two classes of MAPK, p38 and ERK1/2 and link this to the aberrant mGluR-LTD that has an important role in diseases.

      This article is part of the 60th Anniversary special issue.

  22. Reviews

    1. You have free access to this content
      Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance

      Dena G. Hernandez, Xylena Reed and Andrew B. Singleton

      Version of Record online: 18 APR 2016 | DOI: 10.1111/jnc.13593

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      This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets.

      This article is part of a special issue on Parkinson disease.

    2. You have free access to this content
      Cellular models for Parkinson's disease

      Björn H. Falkenburger, Theodora Saridaki and Elisabeth Dinter

      Version of Record online: 18 APR 2016 | DOI: 10.1111/jnc.13618

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      Cellular models reproduce the two most salient changes of Parkinson's disease, the degeneration of dopaminergic neurons and the existence of α-synuclein aggregates. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types and treatments the aspects of Parkinson's disease they model along with technical advantages and disadvantages. Furthermore, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques.

      This article is part of a special issue on Parkinson disease.

    3. You have free access to this content
      ɑ-Synuclein strains and the variable pathologies of synucleinopathies

      Wouter Peelaerts and Veerle Baekelandt

      Version of Record online: 30 MAR 2016 | DOI: 10.1111/jnc.13595

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      Parkinson's disease and other synucleinopathies share ɑ-synuclein deposits as a common histopathological hallmark. New and ongoing developments are now showing that variations in the aggregation process and the formation of ɑ-synuclein strains may be paralleled by the development of distinct synucleinopathies. Here, we review the recent developments and the role of strains in synucleinopathies.

      This article is part of a special issue on Parkinson disease.

    4. You have full text access to this OnlineOpen article
      Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

      Johanna Duda, Christina Pötschke and Birgit Liss

      Version of Record online: 23 MAR 2016 | DOI: 10.1111/jnc.13572

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      We propose that SN DA neurons possess several feedback and feed-forward mechanisms to protect and adapt their activity-pattern and calcium-homeostasis within a physiological bandwidth, and that PD-trigger factors can narrow this bandwidth. We summarize roles of ion channels in this view, and findings documenting that both, reduced as well as elevated activity and associated calcium-levels can trigger SN DA degeneration.

      This article is part of a special issue on Parkinson disease.

    5. You have free access to this content
      MMP-9 in translation: from molecule to brain physiology, pathology, and therapy

      Behnam Vafadari, Ahmad Salamian and Leszek Kaczmarek

      Version of Record online: 21 MAR 2016 | DOI: 10.1111/jnc.13415

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      MMP-9, through cleavage of specific target proteins, plays a major role in synaptic plasticity and neuroinflammation, and by those virtues contributes to brain physiology and a host of neurological and psychiatric disorders.

      This article is part of the 60th Anniversary special issue.

    6. You have free access to this content
      ‘From past to future’ – deciphering the molecular basis of Alzheimer's disease through the pages of the Journal of Neurochemistry

      Roberto Cappai

      Version of Record online: 21 MAR 2016 | DOI: 10.1111/jnc.13546

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      The Journal of Neurochemistry has made significant contributions toward unraveling the molecular, cellular and pathological basis of Alzheimer's disease through its 60 years.

      This article is part of the 60th Anniversary special issue.

    7. You have free access to this content
      The challenges for scientific publishing, 60 years on

      Laura Hausmann, Sean P. Murphy and on behalf of the Publication Committee of the International Society for Neurochemistry (ISN)

      Version of Record online: 21 MAR 2016 | DOI: 10.1111/jnc.13550

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      In the past decades, science publishing underwent dramatic changes in the communication of data and in their interpretation, in the increasing pressure and commercialization, and the democratization of science on a global scale via the Internet. This article reviews the benefits and challenges to publishing including fraudulent behavior and plagiarism, data and statistics reporting standards, authorship confirmation and other issues, with the aim to provide readers with practical examples and hands-on guidelines. As we illustrate here, identifying unacceptable practices leads to changes in the standards for data reporting.

      This article is part of the 60th Anniversary special issue.

    8. You have free access to this content
      Neural plasticity and behavior – sixty years of conceptual advances

      J. David Sweatt

      Version of Record online: 10 MAR 2016 | DOI: 10.1111/jnc.13580

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      The area of neural plasticity and behavior has seen tremendous advances over the last six decades, with many of those advances being specifically in the neurochemistry domain. This review provides an overview of the progress in the area of neuroplasticity and behavior over the life-span of the Journal of Neurochemistry. To organize the broad literature base, the review collates progress into fifteen broad categories identified as ‘conceptual advances’, as viewed by the author. The fifteen areas are delineated in the figure above.

      This article is part of the 60th Anniversary special issue.

  23. Bench to Bedside

    1. Bioenergetics and metabolism: a bench to bedside perspective

      Russell H. Swerdlow

      Version of Record online: 10 MAR 2016 | DOI: 10.1111/jnc.13509

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      A bench-to-bedside biomedical research process is discussed that moves through conceptual, basic, translational, and clinical levels. For example, herein a case was made that bioenergetics is a valid Alzheimer's disease therapeutic target. Following this, a fundamental strategy for manipulating bioenergetics was defined, potential implications studied, and the approach extended to the clinical arena.

      This article is part of the 60th Anniversary special issue.

    2. The next step in translational research: lessons learned from the first preclinical randomized controlled trial

      Gemma Llovera and Arthur Liesz

      Version of Record online: 10 MAR 2016 | DOI: 10.1111/jnc.13516

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      Translational research is hampered by low reproducibility of preclinical studies and countless failed clinical trials. International consortia have proposed preclinical multicenter trials as an intermediate step to overcome this ‘translational roadblock’. We have recently performed the first such preclinical randomized controlled trial (pRCT) by adopting key elements of clinical study design to preclinical research. In this review, we discuss the lessons learned from this trial and provide suggestions how to optimize future pRCTs.

      This article is part of the 60th Anniversary special issue.

    3. Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system

      Douglas L. Feinstein, Sergey Kalinin and David Braun

      Version of Record online: 10 MAR 2016 | DOI: 10.1111/jnc.13447

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      The classical neurotransmitter noradrenaline (NA) has critical roles in modulating behaviors including those involved in sleep, anxiety, and depression. However, NA can also elicit anti-inflammatory responses in glial cells, can increase neuronal viability by inducing neurotrophic factor expression, and can reduce neuronal damage due to oxidative stress by scavenging free radicals. NA is primarily produced by tyrosine hydroxylase (TH) expressing neurons in the locus coeruleus (LC), a relatively small brainstem nucleus near the IVth ventricle which sends projections throughout the brain and spinal cord. It has been known for close to 50 years that LC neurons are lost during normal aging, and that loss is exacerbated in neurological diseases including Parkinson's disease and Alzheimer's disease. LC neuronal damage and glial activation has now been documented in a variety of other neurological conditions and diseases, however, the causes of LC damage and cell loss remain largely unknown. A number of approaches have been developed to address the loss of NA and increased inflammation associated with LC damage, and several methods are being explored to directly minimize the extent of LC neuronal cell loss or function. In this review, we will summarize some of the consequences of LC loss, consider several factors that likely contribute to that loss, and discuss various ways that have been used to increase NA or to reduce LC damage.

      This article is part of the 60th Anniversary special issue.

  24. Past to Future

    1. Proteoglycans and axon guidance: a new relationship between old partners

      Masayuki Masu

      Version of Record online: 10 MAR 2016 | DOI: 10.1111/jnc.13508

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      Neural circuits are formed by the combined actions of axon guidance molecules. Proteoglycans play critical roles in regulating axon guidance through the interaction between signaling molecules and glycosaminoglycan chains attached to the core protein. This paper summarizes the structure and functions of axon guidance molecules and glycosaminoglycans and reviews the molecular mechanisms by which proteoglycans regulate axon guidance from a new vantage point.

      This article is part of the 60th Anniversary special issue.

  25. Supplement Articles

    1. You have full text access to this OnlineOpen article
      Bioenergetics and redox adaptations of astrocytes to neuronal activity

      Juan P. Bolaños

      Version of Record online: 10 MAR 2016 | DOI: 10.1111/jnc.13486

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      Our current knowledge on brain's management of bioenergetics and redox requirements associated with neural activity is herein revisited. The astrocyte-neuronal lactate shuttle (ANLS) explains the energy needs of neurotransmission. Furthermore, neurotransmission unavoidably triggers increased mitochondrial reactive oxygen species in neurons. By coupling glutamatergic activity with transcriptional activation of antioxidant genes, astrocytes provide neurons with neuroprotective glutathione through an astrocyte-neuronal glutathione shuttle (ANGS).

      This article is part of the 60th Anniversary special issue.

  26. Editorial

    1. You have free access to this content
      LRRK2 pathobiology in Parkinson's disease – virtual inclusion

      Ian Martin, Jungwoo Wren Kim, Valina L. Dawson and Ted M. Dawson

      Version of Record online: 22 FEB 2016 | DOI: 10.1111/jnc.13549

      This article is part of a special issue on Parkinson disease.

  27. Reviews

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      Sorting out release, uptake and processing of alpha-synuclein during prion-like spread of pathology

      Trevor Tyson, Jennifer A. Steiner and Patrik Brundin

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/jnc.13449

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      The prion-like hypothesis of α-synuclein pathology suggests a method for the transmission of misfolded α-synuclein from one neuron to another. This hypothesis postulates that misfolded α-synuclein becomes aggregation prone and when released and taken up by neighboring cells, seeds further misfolding and aggregation. In this review we examine the cellular mechanisms that are involved in the processing of α-synuclein and how these may contribute to the prion-like propagation of α-synuclein pathology.

      This article is part of a special issue on Parkinson disease.

  28. Systematic Reviews

    1. You have free access to this content
      Parkinson's disease: acid-glucocerebrosidase activity and alpha-synuclein clearance

      Judith Blanz and Paul Saftig

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/jnc.13517

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      Lysosomes are critical for protein and lipid homeostasis. Recent research revealed that dysfunction of this organelle contributes to the development of neurodegenerative diseases such as Parkinson's disease (PD). Mutations in the lysosomal hydrolase β-glucocerebrosidase (GBA1) are a major risk factor for the development of PD and the molecular events linked to the reduced activity of GBA1 and the pathological accumulation of lipids and α-synuclein are just at the beginning to be understood. New therapeutic concepts in regards to how to increase the expression, stability, or delivery of β-glucocerebrosidase to lysosomes are currently developed.

      This article is part of a special issue on Parkinson disease.

  29. Reviews

    1. You have free access to this content
      Therapeutic approaches in Parkinson's disease and related disorders

      Elvira Valera and Eliezer Masliah

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/jnc.13529

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      Synucleinopathies, neurodegenerative disorders characterized by the abnormal accumulation of the protein alpha-synuclein, constitute the second leading cause of parkinsonism and dementia in the elderly population, however, no disease-modifying options are available yet. In this review, we summarize the therapeutic approaches currently being explored for synucleinopathies, suggest possible explanations to the clinical outcomes, and propose areas of further therapeutic improvement.

      This article is part of a special issue on Parkinson disease.

    2. You have free access to this content
      Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics

      Abdel A. Belaidi and Ashley I. Bush

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/jnc.13425

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      Iron plays a fundamental role in maintaining the high metabolic and energetic requirements of the brain. However, iron has to be maintained in a delicate balance as both iron overload and iron deficiency are detrimental to the brain and can trigger neurodegeneration. Here, we discuss the current knowledge on brain iron homeostasis and its involvement in major aging-related neurodegenerative diseases.

      This article is part of a special issue on Parkinson disease.

    3. You have free access to this content
      Biological confounders for the values of cerebrospinal fluid proteins in Parkinson's disease and related disorders

      Brit Mollenhauer, Lucilla Parnetti, Irena Rektorova, Milica G. Kramberger, Maria Pikkarainen, Walter J. Schulz-Schaeffer, Dag Aarsland, Per Svenningsson, Lucia Farotti, Marcel M. Verbeek and Michael G. Schlossmacher

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/jnc.13390

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      Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. To investigate potential biological confounders of reported CSF levels for α-synuclein (α-Syn), amyloid-β 1-42(Aβ42) and tau protein in Parkinson's disease and related disorders, we reviewed the current literature for known factors that underlie signal variability and speculate on those that have not yet been tested.

  30. Original Articles

    1. The relationship between glucocerebrosidase mutations and Parkinson disease

      Anna Migdalska-Richards and Anthony H. V. Schapira

      Version of Record online: 10 FEB 2016 | DOI: 10.1111/jnc.13385

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      The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin–proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum-associated degradation (ERAD). The prolonged activation of UPR and ERAD subsequently leads to increased apoptosis. The presence of misfolded GCase in the lysosomes together with a reduction in wild-type GCase levels lead to a retardation of alpha-synuclein degradation via chaperone-mediated autophagy (CMA), which subsequently results in alpha-synuclein accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance of autophagosomes, and so their accumulation. GBA1 mutations perturb normal mitochondria functioning by increasing generation of free radical species (ROS) and decreasing adenosine triphosphate (ATP) production, oxygen consumption, and membrane potential. GBA1 mutations also lead to accumulation of dysfunctional and fragmented mitochondria.

      This article is part of a special issue on Parkinson disease.

  31. Reviews

    1. You have free access to this content
      Structure, function and toxicity of alpha-synuclein: the Bermuda triangle in synucleinopathies

      Anna Villar-Piqué, Tomás Lopes da Fonseca and Tiago Fleming Outeiro

      Version of Record online: 11 SEP 2015 | DOI: 10.1111/jnc.13249

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      Alpha-synuclein is the speculated cornerstone of several neurodegenerative disorders known as Synucleinopathies. Nevertheless, the mechanisms underlying the pathogenic effects of this protein remain unknown. Here, we review the recent findings in the three corners of alpha-synuclein biology – structure, function and toxicity – and discuss the enigmatic roads that have accompanied alpha-synuclein from the beginning.

    2. You have free access to this content
      Genes associated with Parkinson's disease: regulation of autophagy and beyond

      Alexandra Beilina and Mark R Cookson

      Version of Record online: 3 SEP 2015 | DOI: 10.1111/jnc.13266

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      Beilina and Cookson review the links between genes for Parkinson's disease (red) and the autophagy–lysosomal system. They propose the hypothesis that many of the known PD genes can be assigned to pathways that affect (I) turnover of mitochondria via mitophagy (II) turnover of several vesicular structures via macroautophagy or chaperone-mediated autophagy or (III) general lysosome function.

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