Arsović, A.; Halbach, M.V.; Canet-Pons, J.; Esen-Sehir, D.; Döring, C.; Freudenberg, F.; Czechowska, N.; Seidel, K.; Baader, S.L.; Gispert, S.; Sen, N.-E.; Auburger, G. Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength. Int. J. Mol. Sci.2020, 21, 6673.
Arsović, A.; Halbach, M.V.; Canet-Pons, J.; Esen-Sehir, D.; Döring, C.; Freudenberg, F.; Czechowska, N.; Seidel, K.; Baader, S.L.; Gispert, S.; Sen, N.-E.; Auburger, G. Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength. Int. J. Mol. Sci. 2020, 21, 6673.
Arsović, A.; Halbach, M.V.; Canet-Pons, J.; Esen-Sehir, D.; Döring, C.; Freudenberg, F.; Czechowska, N.; Seidel, K.; Baader, S.L.; Gispert, S.; Sen, N.-E.; Auburger, G. Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength. Int. J. Mol. Sci.2020, 21, 6673.
Arsović, A.; Halbach, M.V.; Canet-Pons, J.; Esen-Sehir, D.; Döring, C.; Freudenberg, F.; Czechowska, N.; Seidel, K.; Baader, S.L.; Gispert, S.; Sen, N.-E.; Auburger, G. Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength. Int. J. Mol. Sci. 2020, 21, 6673.
Abstract
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, thus exerting crucial neuroprotection for cerebellar ataxias and corticospinal motor neuron degeneration. 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. Earliest changes were detected at 3 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 affected. Systematic screening of pre/post-synapse components, with dendrite morphology assessment, suggested early impairment of CamKIIα abundance together with weakening of parallel fiber connectivity. These data reveal molecular changes due to ATXN2 pathology, impacting communication and excitability of cerebellar neurons. Discovery of such risk versus progression markers improves the assessment of pre-symptomatic treatments in SCA2 and related disorders.
Biology and Life Sciences, Biochemistry and Molecular Biology
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