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      ‘Medusa-head ataxia’: the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: Anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII

      review-article
      ,
      Journal of Neuroinflammation
      BioMed Central
      Autoimmune cerebellar ataxia, Cerebellitis, Paraneoplastic cerebellar degeneration, Autoantibodies, Purkinje cells, Metabotropic glutamate receptor 1 (mGluR1) antibodies, Homer-3 antibodies, Anti-Sj, Inositol 1,4,5-trisphosphate receptor 1 (ITPR1, I3PR) antibodies, Carbonic anhydrase-related protein VIII (CARP VIII) antibodies, Protein kinase gamma (PKCγ) antibodies, Anti-Ca, Rho GTPase-activating protein 26 (ARHGAP26, GRAF) antibodies, Glutamate receptor delta2 (GluRδ2) antibodies, Anti-Yo, Cerebellar degeneration-related protein 2 (CDR2) antibodies, Cerebellar degeneration-related protein 2-like (CDR2L) antibodies, Purkinje cell antibody 2 (PCA-2), Anti-Tr, Delta notch-like epidermal growth factor-related receptor (DNER) antibodies, Anti-Nb, Anti-AP3B2, Neuronal adaptin-like protein (beta-NAP) antibodies, Voltage-gated calcium channel (VGCC) antibodies

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          Abstract

          Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as ‘Medusa-head antibodies’ due to their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects and provides a summary and outlook.

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          Most cited references182

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          Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients

          Background The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. Objective To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. Methods Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). Results Seropositive patients were found to be predominantly female (p 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. Conclusion This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
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            Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.

            Eukaryotic cells respond to many hormones and neurotransmitters with increased activity of the enzyme phospholipase C and a subsequent rise in the concentration of intracellular free calcium ([Ca2+]i). The increase in [Ca2+]i occurs as a result of the release of Ca2+ from intracellular stores and an influx of Ca2+ through the plasma membrane; this influx of Ca2+ may or may not be store-dependent. Drosophila transient receptor potential (TRP) proteins and some mammalian homologues (TRPC proteins) are thought to mediate capacitative Ca2+ entry. Here we describe the molecular mechanism of store-depletion-independent activation of a subfamily of mammalian TRPC channels. We find that hTRPC6 is a non-selective cation channel that is activated by diacylglycerol in a membrane-delimited fashion, independently of protein kinases C activated by diacylglycerol. Although hTRPC3, the closest structural relative of hTRPC6, is activated in the same way, TRPCs 1, 4 and 5 and the vanilloid receptor subtype 1 are unresponsive to the lipid mediator. Thus, hTRPC3 and hTRPC6 represent the first members of a new functional family of second-messenger-operated cation channels, which are activated by diacylglycerol.
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              Homer: a protein that selectively binds metabotropic glutamate receptors.

              Spatial localization and clustering of membrane proteins is critical to neuronal development and synaptic plasticity. Recent studies have identified a family of proteins, the PDZ proteins, that contain modular PDZ domains and interact with synaptic ionotropic glutamate receptors and ion channels. PDZ proteins are thought to have a role in defining the cellular distribution of the proteins that interact with them. Here we report a novel dendritic protein, Homer, that contains a single, PDZ-like domain and binds specifically to the carboxy terminus of phosphoinositide-linked metabotropic glutamate receptors. Homer is highly divergent from known PDZ proteins and seems to represent a novel family. The Homer gene is also distinct from members of the PDZ family in that its expression is regulated as an immediate early gene and is dynamically responsive to physiological synaptic activity, particularly during cortical development. This dynamic transcriptional control suggests that Homer mediates a novel cellular mechanism that regulates metabotropic glutamate signalling.
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                Author and article information

                Contributors
                +49-6221-56-4747 , sven.jarius@med.uni-heidelberg.de , sjarius@med.uni-heidelberg.de
                brigitte.wildemann@med.uni-heidelberg.de
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                17 September 2015
                17 September 2015
                2015
                : 12
                : 166
                Affiliations
                Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Otto Meyerhof Center, Im Neuenheimer Feld 350, D-69120 Heidelberg, Germany
                Article
                356
                10.1186/s12974-015-0356-y
                4574226
                26377085
                632a50c7-84c8-4dcb-ab20-6c9b024f2616
                © Jarius and Wildemann. 2015

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 May 2015
                : 2 July 2015
                Categories
                Review
                Custom metadata
                © The Author(s) 2015

                Neurosciences
                autoimmune cerebellar ataxia,cerebellitis,paraneoplastic cerebellar degeneration,autoantibodies,purkinje cells,metabotropic glutamate receptor 1 (mglur1) antibodies,homer-3 antibodies,anti-sj,inositol 1,4,5-trisphosphate receptor 1 (itpr1, i3pr) antibodies,carbonic anhydrase-related protein viii (carp viii) antibodies,protein kinase gamma (pkcγ) antibodies,anti-ca,rho gtpase-activating protein 26 (arhgap26, graf) antibodies,glutamate receptor delta2 (glurδ2) antibodies,anti-yo,cerebellar degeneration-related protein 2 (cdr2) antibodies,cerebellar degeneration-related protein 2-like (cdr2l) antibodies,purkinje cell antibody 2 (pca-2),anti-tr,delta notch-like epidermal growth factor-related receptor (dner) antibodies,anti-nb,anti-ap3b2,neuronal adaptin-like protein (beta-nap) antibodies,voltage-gated calcium channel (vgcc) antibodies

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