TY  - JOUR
A1  - Arsović, Aleksandar
A1  - Halbach, Melanie Vanessa
A1  - Canet Pons, Júlia
A1  - Esen-Sehir, Dilhan
A1  - Döring, Claudia
A1  - Freudenberg, Florian
A1  - Czechowska, Nicoletta
A1  - Seidel, Kay
A1  - Baader, Stephan L.
A1  - Gispert, Suzana
A1  - Şen, Nesli Ece
A1  - Auburger, Georg
T1  - Mouse Ataxin-2 expansion downregulates CamKII and other calcium signaling factors, impairing granule—Purkinje neuron synaptic strength
T2  - International journal of molecular sciences
N2  - 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.
KW  - amyotrophic lateral sclerosis (ALS)
KW  - fronto-temporal-lobar-dementia
KW  - tauopathies
KW  - synaptic plasticity
KW  - long-term potentiation
KW  - spatial learning
KW  - inositol signaling
KW  - neurexin
KW  - K-homology RNA-binding domain
KW  - fragile-X-associated tremor-ataxia syndrome
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/56127
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-561274
SN  - 1422-0067
N1  - © 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 (http://creativecommons.org/licenses/by/4.0/).
VL  - 21
IS  - 18, art. 6673
SP  - 1
EP  - 36
PB  - MDPI
CY  - Basel
ER  -