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

Aleksandar Arsović,Georg Auburger,Claudia Döring,Júlia Canet-Pons,Stephan L Baader,Melanie Vanessa Halbach,Nesli-Ece Sen,Suzana Gispert,Dilhan Esen-Sehir,Florian Freudenberg,Nicoletta Czechowska,Kay Seidel

doi:10.3390/ijms21186673

Aleksandar Arsović, Georg Auburger + Show 10 more

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https://doi.org/10.3390/ijms21186673

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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. 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.

Highlights

Spinocerebellar ataxia type 2 (SCA2) is an autosomal-dominantly inherited neurodegenerative disorder, caused by repeat expansion mutations in the ataxin-2 (ATXN2) poly-glutamine domain [1,2,3]
Considering that the dataset comes from an age before the onset of motor deficits, and that the relevant dysregulations will not be massive at this stage, we empirically set a low 35% expression dysregulation threshold for data filtering, as already successfully done for Parkinson’s disease [57], instead of the commonly used 50% threshold
The upregulated transcript group was dominated by the alteration of some of the hundreds of olfactory and vomeronasal receptors, whose number reflects the importance of smell for rodents, but are irrelevant for SCA2 patients

Summary

Introduction

Spinocerebellar ataxia type 2 (SCA2) is an autosomal-dominantly inherited neurodegenerative disorder, caused by repeat expansion mutations in the ataxin-2 (ATXN2) poly-glutamine domain (polyQ, encoded by CAG repeats at the DNA level) [1,2,3]. Longer expansion sizes lead to earlier manifestation and faster progression of the disease [8]. Intermediate size expansions between 27–33 repeats, often with the preservation of one CAA interruption within the otherwise pure CAG repeat, were reported to increase the risk of developing other neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Parkinsonism-plus syndromes [9,10,11,12]

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