Next Article in Journal
Reply: “Comment on: Food for Bone: Evidence for a Role for Delta-Tocotrienol in the Physiological Control of Osteoblast Migration. Int. J. Mol. Sci. 2020, 21, 4661”
Previous Article in Journal
Engineered Fragments of the PSMA-Specific 5D3 Antibody and Their Functional Characterization
Open AccessArticle

Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength

1
Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
2
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Medical Faculty, Goethe University, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt am Main, Germany
3
Faculty of Biosciences, Goethe-University, Max von Laue Strasse 9, 60438 Frankfurt am Main, Germany
4
Dr. Senckenberg Institute of Pathology, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
5
Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53115 Bonn, Germany
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(18), 6673; https://doi.org/10.3390/ijms21186673
Received: 20 August 2020 / Revised: 7 September 2020 / Accepted: 10 September 2020 / Published: 12 September 2020
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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. View Full-Text
Keywords: amyotrophic lateral sclerosis (ALS); fronto-temporal-lobar-dementia; tauopathies; synaptic plasticity; long-term potentiation; spatial learning; inositol signaling; neurexin; K-homology RNA-binding domain; fragile-X-associated tremor-ataxia syndrome amyotrophic lateral sclerosis (ALS); fronto-temporal-lobar-dementia; tauopathies; synaptic plasticity; long-term potentiation; spatial learning; inositol signaling; neurexin; K-homology RNA-binding domain; fragile-X-associated tremor-ataxia syndrome
Show Figures

Figure 1

MDPI and ACS Style

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.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop