{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T22:30:51Z","timestamp":1775082651948,"version":"3.50.1"},"reference-count":101,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,12]],"date-time":"2020-09-12T00:00:00Z","timestamp":1599868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["AU96\/11-1, AU96\/11-3, FR3420\/2-2, INST1172\/37-1"],"award-info":[{"award-number":["AU96\/11-1, AU96\/11-3, FR3420\/2-2, INST1172\/37-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013Sam68 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 CamKII\u03b1 abundance together with the weakening of parallel fiber connectivity. These data reveal molecular changes due to ATXN2 pathology, primarily impacting excitability and communication.<\/jats:p>","DOI":"10.3390\/ijms21186673","type":"journal-article","created":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T21:11:32Z","timestamp":1600031492000},"page":"6673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule\u2014Purkinje Neuron Synaptic Strength"],"prefix":"10.3390","volume":"21","author":[{"given":"Aleksandar","family":"Arsovi\u0107","sequence":"first","affiliation":[{"name":"Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie Vanessa","family":"Halbach","sequence":"additional","affiliation":[{"name":"Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00falia","family":"Canet-Pons","sequence":"additional","affiliation":[{"name":"Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4032-8807","authenticated-orcid":false,"given":"Dilhan","family":"Esen-Sehir","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Medical Faculty, Goethe University, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt am Main, Germany"},{"name":"Faculty of Biosciences, Goethe-University, Max von Laue Strasse 9, 60438 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"D\u00f6ring","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Pathology, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1438-3850","authenticated-orcid":false,"given":"Florian","family":"Freudenberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Medical Faculty, Goethe University, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicoletta","family":"Czechowska","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53115 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kay","family":"Seidel","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53115 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan L.","family":"Baader","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53115 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzana","family":"Gispert","sequence":"additional","affiliation":[{"name":"Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nesli-Ece","family":"Sen","sequence":"additional","affiliation":[{"name":"Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"},{"name":"Faculty of Biosciences, Goethe-University, Max von Laue Strasse 9, 60438 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Auburger","sequence":"additional","affiliation":[{"name":"Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/ng1196-269","article-title":"Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2","volume":"14","author":"Pulst","year":"1996","journal-title":"Nat. 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