Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity

Abstract The neuronal membrane-associated periodic spectrin skeleton (MPS) contributes to neuronal development, remodeling, and organization. Post-translational modifications impinge on spectrin, the major component of the MPS, but their role remains poorly understood. One modification targeting spe...

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Autores principales:	Arkadiusz Miazek, Michał Zalas, Joanna Skrzymowska, Bryan A. Bogin, Krzysztof Grzymajło, Tomasz M. Goszczynski, Zachary A. Levine, Jon S. Morrow, Michael C. Stankewich
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/40927af2976845f3a475e0d8a41ea927
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spelling	oai:doaj.org-article:40927af2976845f3a475e0d8a41ea9272021-12-02T18:17:53ZAge-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity10.1038/s41598-021-86470-12045-2322https://doaj.org/article/40927af2976845f3a475e0d8a41ea9272021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86470-1https://doaj.org/toc/2045-2322Abstract The neuronal membrane-associated periodic spectrin skeleton (MPS) contributes to neuronal development, remodeling, and organization. Post-translational modifications impinge on spectrin, the major component of the MPS, but their role remains poorly understood. One modification targeting spectrin is cleavage by calpains, a family of calcium-activated proteases. Spectrin cleavage is regulated by activated calpain, but also by the calcium-dependent binding of calmodulin (CaM) to spectrin. The physiologic significance of this balance between calpain activation and substrate-level regulation of spectrin cleavage is unknown. We report a strain of C57BL/6J mice harboring a single αII spectrin point mutation (Sptan1 c.3293G > A:p.R1098Q) with reduced CaM affinity and intrinsically enhanced sensitivity to calpain proteolysis. Homozygotes are embryonic lethal. Newborn heterozygotes of either gender appear normal, but soon develop a progressive ataxia characterized biochemically by accelerated calpain-mediated spectrin cleavage and morphologically by disruption of axonal and dendritic integrity and global neurodegeneration. Molecular modeling predicts unconstrained exposure of the mutant spectrin’s calpain-cleavage site. These results reveal the critical importance of substrate-level regulation of spectrin cleavage for the maintenance of neuronal integrity. Given that excessive activation of calpain proteases is a common feature of neurodegenerative disease and traumatic encephalopathy, we propose that damage to the spectrin MPS may contribute to the neuropathology of many disorders.Arkadiusz MiazekMichał ZalasJoanna SkrzymowskaBryan A. BoginKrzysztof GrzymajłoTomasz M. GoszczynskiZachary A. LevineJon S. MorrowMichael C. StankewichNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Arkadiusz Miazek Michał Zalas Joanna Skrzymowska Bryan A. Bogin Krzysztof Grzymajło Tomasz M. Goszczynski Zachary A. Levine Jon S. Morrow Michael C. Stankewich Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity
description	Abstract The neuronal membrane-associated periodic spectrin skeleton (MPS) contributes to neuronal development, remodeling, and organization. Post-translational modifications impinge on spectrin, the major component of the MPS, but their role remains poorly understood. One modification targeting spectrin is cleavage by calpains, a family of calcium-activated proteases. Spectrin cleavage is regulated by activated calpain, but also by the calcium-dependent binding of calmodulin (CaM) to spectrin. The physiologic significance of this balance between calpain activation and substrate-level regulation of spectrin cleavage is unknown. We report a strain of C57BL/6J mice harboring a single αII spectrin point mutation (Sptan1 c.3293G > A:p.R1098Q) with reduced CaM affinity and intrinsically enhanced sensitivity to calpain proteolysis. Homozygotes are embryonic lethal. Newborn heterozygotes of either gender appear normal, but soon develop a progressive ataxia characterized biochemically by accelerated calpain-mediated spectrin cleavage and morphologically by disruption of axonal and dendritic integrity and global neurodegeneration. Molecular modeling predicts unconstrained exposure of the mutant spectrin’s calpain-cleavage site. These results reveal the critical importance of substrate-level regulation of spectrin cleavage for the maintenance of neuronal integrity. Given that excessive activation of calpain proteases is a common feature of neurodegenerative disease and traumatic encephalopathy, we propose that damage to the spectrin MPS may contribute to the neuropathology of many disorders.
format	article
author	Arkadiusz Miazek Michał Zalas Joanna Skrzymowska Bryan A. Bogin Krzysztof Grzymajło Tomasz M. Goszczynski Zachary A. Levine Jon S. Morrow Michael C. Stankewich
author_facet	Arkadiusz Miazek Michał Zalas Joanna Skrzymowska Bryan A. Bogin Krzysztof Grzymajło Tomasz M. Goszczynski Zachary A. Levine Jon S. Morrow Michael C. Stankewich
author_sort	Arkadiusz Miazek
title	Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity
title_short	Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity
title_full	Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity
title_fullStr	Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity
title_full_unstemmed	Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity
title_sort	age-dependent ataxia and neurodegeneration caused by an αii spectrin mutation with impaired regulation of its calpain sensitivity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/40927af2976845f3a475e0d8a41ea927
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Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity

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