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 (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.
Author:Aleksandar ArsovićORCiD, Melanie Vanessa HalbachGND, Júlia Canet PonsORCiD, Dilhan Esen-SehirORCiD, Claudia DöringGND, Florian FreudenbergORCiDGND, Nicoletta Czechowska, Kay Seidel, Stephan L. Baader, Suzana Gispert, Nesli Ece ŞenGND, Georg AuburgerORCiDGND
Parent Title (English):International journal of molecular sciences
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/09/12
Date of first Publication:2020/09/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/09/24
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
Issue:18, art. 6673
Page Number:36
First Page:1
Last Page:36
© 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 (
Biowissenschaften / Biowissenschaften
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0