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Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength
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 (Ca(2+)) homeostasis after stimuli. Cerebellar ataxias and corticospinal motor neuron degeneration are determined by...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555182/ https://www.ncbi.nlm.nih.gov/pubmed/32932600 http://dx.doi.org/10.3390/ijms21186673 |
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author | Arsović, Aleksandar Halbach, Melanie Vanessa Canet-Pons, Júlia Esen-Sehir, Dilhan Döring, Claudia Freudenberg, Florian Czechowska, Nicoletta Seidel, Kay Baader, Stephan L. Gispert, Suzana Sen, Nesli-Ece Auburger, Georg |
author_facet | Arsović, Aleksandar Halbach, Melanie Vanessa Canet-Pons, Júlia Esen-Sehir, Dilhan Döring, Claudia Freudenberg, Florian Czechowska, Nicoletta Seidel, Kay Baader, Stephan L. Gispert, Suzana Sen, Nesli-Ece Auburger, Georg |
author_sort | Arsović, Aleksandar |
collection | PubMed |
description | 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 (Ca(2+)) 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 Ca(2+) channels/transporters (Itpr1, Ryr3, Atp2a2, Atp2a3, Trpc3), IP(3) metabolism (Plcg1, Inpp5a, Itpka), and Ca(2+)-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. |
format | Online Article Text |
id | pubmed-7555182 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75551822020-10-19 Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength Arsović, Aleksandar Halbach, Melanie Vanessa Canet-Pons, Júlia Esen-Sehir, Dilhan Döring, Claudia Freudenberg, Florian Czechowska, Nicoletta Seidel, Kay Baader, Stephan L. Gispert, Suzana Sen, Nesli-Ece Auburger, Georg Int J Mol Sci Article 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 (Ca(2+)) 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 Ca(2+) channels/transporters (Itpr1, Ryr3, Atp2a2, Atp2a3, Trpc3), IP(3) metabolism (Plcg1, Inpp5a, Itpka), and Ca(2+)-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. MDPI 2020-09-12 /pmc/articles/PMC7555182/ /pubmed/32932600 http://dx.doi.org/10.3390/ijms21186673 Text en © 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/). |
spellingShingle | Article Arsović, Aleksandar Halbach, Melanie Vanessa Canet-Pons, Júlia Esen-Sehir, Dilhan Döring, Claudia Freudenberg, Florian Czechowska, Nicoletta Seidel, Kay Baader, Stephan L. Gispert, Suzana Sen, Nesli-Ece Auburger, Georg Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength |
title | Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength |
title_full | Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength |
title_fullStr | Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength |
title_full_unstemmed | Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength |
title_short | Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength |
title_sort | mouse ataxin-2 expansion downregulates camkii and other calcium signaling factors, impairing granule—purkinje neuron synaptic strength |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555182/ https://www.ncbi.nlm.nih.gov/pubmed/32932600 http://dx.doi.org/10.3390/ijms21186673 |
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