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Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is an intractable progressive neurodegenerative disease that leads to a range of movement and motor defects and is eventually lethal. Purkinje cells (PC) are typically the first to show signs of degeneration. SCA1 is caused by an expansion of the polyglutamine tr...

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Autores principales: Shuvaev, Anton N., Belozor, Olga S., Mozhei, Oleg I., Shuvaev, Andrey N., Fritsler, Yana V., Khilazheva, Elena D., Mosyagina, Angelina I., Hirai, Hirokazu, Teschemacher, Anja G., Kasparov, Sergey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317252/
https://www.ncbi.nlm.nih.gov/pubmed/35883691
http://dx.doi.org/10.3390/cells11142247
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author Shuvaev, Anton N.
Belozor, Olga S.
Mozhei, Oleg I.
Shuvaev, Andrey N.
Fritsler, Yana V.
Khilazheva, Elena D.
Mosyagina, Angelina I.
Hirai, Hirokazu
Teschemacher, Anja G.
Kasparov, Sergey
author_facet Shuvaev, Anton N.
Belozor, Olga S.
Mozhei, Oleg I.
Shuvaev, Andrey N.
Fritsler, Yana V.
Khilazheva, Elena D.
Mosyagina, Angelina I.
Hirai, Hirokazu
Teschemacher, Anja G.
Kasparov, Sergey
author_sort Shuvaev, Anton N.
collection PubMed
description Spinocerebellar ataxia type 1 (SCA1) is an intractable progressive neurodegenerative disease that leads to a range of movement and motor defects and is eventually lethal. Purkinje cells (PC) are typically the first to show signs of degeneration. SCA1 is caused by an expansion of the polyglutamine tract in the ATXN1 gene and the subsequent buildup of mutant Ataxin-1 protein. In addition to its toxicity, mutant Ataxin-1 protein interferes with gene expression and signal transduction in cells. Recently, it is evident that ATXN1 is not only expressed in neurons but also in glia, however, it is unclear the extent to which either contributes to the overall pathology of SCA1. There are various ways to model SCA1 in mice. Here, functional deficits at cerebellar synapses were investigated in two mouse models of SCA1 in which mutant ATXN1 is either nonspecifically expressed in all cell types of the cerebellum (SCA1 knock-in (KI)), or specifically in Bergmann glia with lentiviral vectors expressing mutant ATXN1 under the control of the astrocyte-specific GFAP promoter. We report impairment of motor performance in both SCA1 models. In both cases, prominent signs of astrocytosis were found using immunohistochemistry. Electrophysiological experiments revealed alteration of presynaptic plasticity at synapses between parallel fibers and PCs, and climbing fibers and PCs in SCA1 KI mice, which is not observed in animals expressing mutant ATXN1 solely in Bergmann glia. In contrast, short- and long-term synaptic plasticity was affected in both SCA1 KI mice and glia-targeted SCA1 mice. Thus, non-neuronal mechanisms may underlie some aspects of SCA1 pathology in the cerebellum. By combining the outcomes of our current work with our previous data from the B05 SCA1 model, we further our understanding of the mechanisms of SCA1.
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spelling pubmed-93172522022-07-27 Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1 Shuvaev, Anton N. Belozor, Olga S. Mozhei, Oleg I. Shuvaev, Andrey N. Fritsler, Yana V. Khilazheva, Elena D. Mosyagina, Angelina I. Hirai, Hirokazu Teschemacher, Anja G. Kasparov, Sergey Cells Article Spinocerebellar ataxia type 1 (SCA1) is an intractable progressive neurodegenerative disease that leads to a range of movement and motor defects and is eventually lethal. Purkinje cells (PC) are typically the first to show signs of degeneration. SCA1 is caused by an expansion of the polyglutamine tract in the ATXN1 gene and the subsequent buildup of mutant Ataxin-1 protein. In addition to its toxicity, mutant Ataxin-1 protein interferes with gene expression and signal transduction in cells. Recently, it is evident that ATXN1 is not only expressed in neurons but also in glia, however, it is unclear the extent to which either contributes to the overall pathology of SCA1. There are various ways to model SCA1 in mice. Here, functional deficits at cerebellar synapses were investigated in two mouse models of SCA1 in which mutant ATXN1 is either nonspecifically expressed in all cell types of the cerebellum (SCA1 knock-in (KI)), or specifically in Bergmann glia with lentiviral vectors expressing mutant ATXN1 under the control of the astrocyte-specific GFAP promoter. We report impairment of motor performance in both SCA1 models. In both cases, prominent signs of astrocytosis were found using immunohistochemistry. Electrophysiological experiments revealed alteration of presynaptic plasticity at synapses between parallel fibers and PCs, and climbing fibers and PCs in SCA1 KI mice, which is not observed in animals expressing mutant ATXN1 solely in Bergmann glia. In contrast, short- and long-term synaptic plasticity was affected in both SCA1 KI mice and glia-targeted SCA1 mice. Thus, non-neuronal mechanisms may underlie some aspects of SCA1 pathology in the cerebellum. By combining the outcomes of our current work with our previous data from the B05 SCA1 model, we further our understanding of the mechanisms of SCA1. MDPI 2022-07-20 /pmc/articles/PMC9317252/ /pubmed/35883691 http://dx.doi.org/10.3390/cells11142247 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shuvaev, Anton N.
Belozor, Olga S.
Mozhei, Oleg I.
Shuvaev, Andrey N.
Fritsler, Yana V.
Khilazheva, Elena D.
Mosyagina, Angelina I.
Hirai, Hirokazu
Teschemacher, Anja G.
Kasparov, Sergey
Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1
title Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1
title_full Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1
title_fullStr Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1
title_full_unstemmed Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1
title_short Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1
title_sort indirect negative effect of mutant ataxin-1 on short- and long-term synaptic plasticity in mouse models of spinocerebellar ataxia type 1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317252/
https://www.ncbi.nlm.nih.gov/pubmed/35883691
http://dx.doi.org/10.3390/cells11142247
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