Aleksandar Arsović, Melanie Vanessa Halbach, Júlia Canet Pons, Dilhan Esen-Sehir, Claudia Döring, Florian Freudenberg, Nicoletta Czechowska, Kay Seidel, Stephan L. Baader, Suzana Gispert, Nesli Ece Şen, Georg Auburger
- Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine expansion in Ataxin-2 (ATXN2). This factor binds RNA/proteins to modify metabolism after stress, and to control calcium (Ca2+) homeostasis after stimuli. Cerebellar ataxias and corticospinal motor neuron degeneration are determined by gain/loss in ATXN2 function, so we aimed to identify key molecules in this atrophic process, as potential disease progression markers. Our Atxn2-CAG100-Knock-In mouse faithfully models features observed in patients at pre-onset, early and terminal stages. Here, its cerebellar global RNA profiling revealed downregulation of signaling cascades to precede motor deficits. Validation work at mRNA/protein level defined alterations that were independent of constant physiological ATXN2 functions, but specific for RNA/aggregation toxicity, and progressive across the short lifespan. The earliest changes were detected at three months among Ca2+ channels/transporters (Itpr1, Ryr3, Atp2a2, Atp2a3, Trpc3), IP3 metabolism (Plcg1, Inpp5a, Itpka), and Ca2+-Calmodulin dependent kinases (Camk2a, Camk4). CaMKIV–Sam68 control over alternative splicing of Nrxn1, an adhesion component of glutamatergic synapses between granule and Purkinje neurons, was found to be affected. Systematic screening of pre/post-synapse components, with dendrite morphology assessment, suggested early impairment of CamKIIα abundance together with the weakening of parallel fiber connectivity. These data reveal molecular changes due to ATXN2 pathology, primarily impacting excitability and communication.
MetadatenAuthor: | Aleksandar ArsovićORCiD, Melanie Vanessa HalbachGND, Júlia Canet PonsORCiD, Dilhan Esen-SehirORCiD, Claudia DöringORCiDGND, Florian FreudenbergORCiDGND, Nicoletta Czechowska, Kay Seidel, Stephan L. Baader, Suzana Gispert, Nesli Ece ŞenGND, Georg AuburgerORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-561274 |
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DOI: | https://doi.org/10.3390/ijms21186673 |
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ISSN: | 1422-0067 |
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Parent Title (English): | International journal of molecular sciences |
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Publisher: | MDPI |
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Place of publication: | Basel |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2020/09/12 |
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Date of first Publication: | 2020/09/12 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2020/09/24 |
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Tag: | K-homology RNA-binding domain; amyotrophic lateral sclerosis (ALS); fragile-X-associated tremor-ataxia syndrome; fronto-temporal-lobar-dementia; inositol signaling; long-term potentiation; neurexin; spatial learning; synaptic plasticity; tauopathies |
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Volume: | 21 |
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Issue: | 18, art. 6673 |
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Page Number: | 36 |
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First Page: | 1 |
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Last Page: | 36 |
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Note: | © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
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HeBIS-PPN: | 470773480 |
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Institutes: | Medizin |
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| Biowissenschaften / Biowissenschaften |
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Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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| 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Open-Access-Publikationsfonds: | Medizin |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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