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

• Published in: International journal of molecular sciences 2020-09, Vol.21 (18), p.6673
• Main Authors: Arsović, Aleksandar, Halbach, Melanie Vanessa, Canet-Pons, Júlia, Esen-Sehir, Dilhan, Döring, Claudia, Freudenberg, Florian, Czechowska, Nicoletta, Seidel, Kay, Baader, Stephan L, Gispert, Suzana, Sen, Nesli-Ece, Auburger, Georg
• Format: Article
• Language: English
• Subjects: Age; Alternative splicing; Amyotrophic lateral sclerosis; amyotrophic lateral sclerosis (ALS); Animal models; Animals; Ataxia; Ataxin; Ataxin-2 - genetics; Ca2+/calmodulin-dependent protein kinase II; Ca2+/calmodulin-dependent protein kinase IV; Calcium channels; Calcium homeostasis; Calcium ions; Calcium Signaling - genetics; Calcium signalling; Calcium-binding protein; Calcium-Binding Proteins - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calmodulin; Cells, Cultured; Cerebellum; Cerebellum - physiology; Degeneration; Dendritic structure; Down-Regulation - genetics; fronto-temporal-lobar-dementia; Glutamatergic transmission; Granular materials; Homeostasis; Kinases; Life span; long-term potentiation; Metabolism; Mice; Mice, Knockout; mRNA; Mutation; Neural networks; Neurodegeneration; Neurons; Pathology; Polyglutamine; Proteins; Purkinje cells; Purkinje Cells - physiology; Pyramidal tracts; RNA, Messenger - genetics; Ryanodine receptors; spatial learning; Spinal cord; Splicing; Synapses; Synapses - genetics; synaptic plasticity; Synaptic strength; tauopathies; Toxicity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21186673

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 (Ca ) 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 -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 Ca channels/transporters ( , , , , ), IP metabolism ( , , ), and Ca -Calmodulin dependent kinases ( , ). CaMKIV-Sam68 control over alternative splicing of , 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.