دورية أكاديمية
Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength
العنوان: | Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength |
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المؤلفون: | 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 Sen, Georg Auburger |
المصدر: | International Journal of Molecular Sciences, Vol 21, Iss 18, p 6673 (2020) |
بيانات النشر: | MDPI AG, 2020. |
سنة النشر: | 2020 |
المجموعة: | LCC:Biology (General) LCC:Chemistry |
مصطلحات موضوعية: | amyotrophic lateral sclerosis (ALS), fronto-temporal-lobar-dementia, tauopathies, synaptic plasticity, long-term potentiation, spatial learning, Biology (General), QH301-705.5, Chemistry, QD1-999 |
الوصف: | 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. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 1422-0067 1661-6596 |
العلاقة: | https://www.mdpi.com/1422-0067/21/18/6673Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test |
DOI: | 10.3390/ijms21186673 |
الوصول الحر: | https://doaj.org/article/e9d428c64c004927914ea5f2ecf98dd6Test |
رقم الانضمام: | edsdoj.9d428c64c004927914ea5f2ecf98dd6 |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 14220067 16616596 |
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DOI: | 10.3390/ijms21186673 |