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Cognitive Decline and Mood Alterations in the Mouse Model of Spinocerebellar Ataxia Type 2

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Abstract

Spinocerebellar ataxia type 2 (SCA2) is a hereditary disorder, caused by an expansion of polyglutamine in the ataxin-2 protein. Although the mutant protein is expressed throughout all the cell and organ types, the cerebellum is primarily affected. The disease progression is mainly accompanied by a decline in motor functions. However, the disturbances in cognitive abilities and low mental state have also been reported in patients. Recent evidence suggests that the cerebellar functionality expands beyond the motor control. Thus, the cerebellum turned out to be involved into the language, verbal working, and spatial memory; executive functions such as working memory, planning, organizing, and strategy formation; and emotional processing. Here, we used the transgenic SCA2-58Q mice to evaluate their anxiety, cognitive functions, and mood alterations. The expression of the mutant ataxin-2 specifically in the cerebellar Purkinje cells (PCs) in SCA2-58Q mice allowed us to study the direct involvement of the cerebellum into the cognitive and affective control. We determined that SCA2-58Q mice exhibit anxiolytic behavior, decline in spatial memory, and a depressive-like state. Our results support the idea of cerebellar involvement in cognitive control and the handling of emotions.

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Data Availability

Materials availability—this study did not generate new unique reagents. Data are available upon request.

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Acknowledgements

We are grateful to members of the Laboratory of Molecular Neurodegeneration for advice and suggestions, to John E. Roberts III for technical assistance and encouragement, and to Anastasia V. Bolshakova for administrative assistance. IB is a holder of the Carl J. and Hortense M. Thomsen Chair in Alzheimer’s Disease Research.

Funding

This work was supported by the Russian Science Foundation Grant 22–75-10030 (PE) and by the National Institutes of Health grant R33NS101182 (IB). The financial support was divided in the following way: research work related to Figs. 1, 2, 3, 4, 5, 6, 7, 8, and 9 was supported by the Russian Science Foundation Grant 22–75-10030, and the publication fee was supported by the NIH grant.

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Authors and Affiliations

  1. Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, Saint Petersburg, Russia

    Ksenia S. Marinina, Ilya B. Bezprozvanny & Polina A. Egorova

  2. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Ilya B. Bezprozvanny

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  1. Ksenia S. Marinina
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Contributions

Conceptualization: P.E and I.B. Data curation: K.M. and P.E. Funding acquisition: P.E. and I.B. Formal Analysis: K.M. and P.E. Investigation: K.M. and P.E Methodology: K.M. and P.E. Project administration: P.E. and I.B. Resources: P.E. and I.B. Software: K.M. and P.E. Supervision: I.B. Validation: K.M. and P.E. Visualization: K.M. and P.E. Writing—original draft: K.M.and P.E. Writing—review and editing: P.E. and I.B.

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Correspondence to Ilya B. Bezprozvanny or Polina A. Egorova.

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All experimental protocols were approved by the Bioethics Committee of the Peter the Great St. Petersburg Polytechnic University at St. Petersburg, Russia, and followed the principles of the European convention (Strasbourg, 1986) and the Declaration of International medical association about the humane treatment of animals (Helsinki, 1996). All methods were carried out in accordance with relevant guidelines and regulations. The study was carried out in compliance with the ARRIVE guidelines.

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Marinina, K.S., Bezprozvanny, I.B. & Egorova, P.A. Cognitive Decline and Mood Alterations in the Mouse Model of Spinocerebellar Ataxia Type 2. Cerebellum 23, 145–161 (2024). https://doi.org/10.1007/s12311-023-01520-w

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