Targeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities

Abstract Calcium dysregulation often underlies pathologies associated with aging and age-associated neurodegenerative diseases. Cells express a unique pattern of Ca2+ channels and pumps geared to fulfill specific physiological requirements and there is a decline in the fidelity of these processes wi...

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Autores principales:	Joshua Goldberg, Antonio Currais, Gamze Ates, Ling Huang, Maxim Shokhirev, Pamela Maher, David Schubert
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/aab8f71534334401ab0fe2d1f969c108
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spelling	oai:doaj.org-article:aab8f71534334401ab0fe2d1f969c1082021-12-02T16:35:11ZTargeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities10.1038/s41514-020-00048-12056-3973https://doaj.org/article/aab8f71534334401ab0fe2d1f969c1082020-08-01T00:00:00Zhttps://doi.org/10.1038/s41514-020-00048-1https://doaj.org/toc/2056-3973Abstract Calcium dysregulation often underlies pathologies associated with aging and age-associated neurodegenerative diseases. Cells express a unique pattern of Ca2+ channels and pumps geared to fulfill specific physiological requirements and there is a decline in the fidelity of these processes with age and age-associated diseases. J147 is an Alzheimer’s disease (AD) drug candidate that was identified using a phenotypic screening platform based upon age-related brain toxicities that are mediated by changes in calcium metabolism. The molecular target for J147 is the α-F1-ATP synthase (ATP5A). J147 has therapeutic efficacy in multiple mouse models of AD and accelerated aging and extends life span in flies. A bioinformatics analysis of gene expression in rapidly aging SAMP8 mice during the last quadrant of their life span shows that J147 has a significant effect on ion transport pathways that are changed with aging, making their expression look more like that of younger animals. The molecular basis of these changes was then investigated in cell culture neurotoxicity assays that were the primary screen in the development of J147. Here we show that J147 and its molecular target, ATP synthase, regulate the maintenance of store-operated calcium entry (SOCE) and cell death during acute neurotoxicity.Joshua GoldbergAntonio CurraisGamze AtesLing HuangMaxim ShokhirevPamela MaherDavid SchubertNature PortfolioarticleGeriatricsRC952-954.6ENnpj Aging and Mechanisms of Disease, Vol 6, Iss 1, Pp 1-9 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Geriatrics RC952-954.6
spellingShingle	Geriatrics RC952-954.6 Joshua Goldberg Antonio Currais Gamze Ates Ling Huang Maxim Shokhirev Pamela Maher David Schubert Targeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities
description	Abstract Calcium dysregulation often underlies pathologies associated with aging and age-associated neurodegenerative diseases. Cells express a unique pattern of Ca2+ channels and pumps geared to fulfill specific physiological requirements and there is a decline in the fidelity of these processes with age and age-associated diseases. J147 is an Alzheimer’s disease (AD) drug candidate that was identified using a phenotypic screening platform based upon age-related brain toxicities that are mediated by changes in calcium metabolism. The molecular target for J147 is the α-F1-ATP synthase (ATP5A). J147 has therapeutic efficacy in multiple mouse models of AD and accelerated aging and extends life span in flies. A bioinformatics analysis of gene expression in rapidly aging SAMP8 mice during the last quadrant of their life span shows that J147 has a significant effect on ion transport pathways that are changed with aging, making their expression look more like that of younger animals. The molecular basis of these changes was then investigated in cell culture neurotoxicity assays that were the primary screen in the development of J147. Here we show that J147 and its molecular target, ATP synthase, regulate the maintenance of store-operated calcium entry (SOCE) and cell death during acute neurotoxicity.
format	article
author	Joshua Goldberg Antonio Currais Gamze Ates Ling Huang Maxim Shokhirev Pamela Maher David Schubert
author_facet	Joshua Goldberg Antonio Currais Gamze Ates Ling Huang Maxim Shokhirev Pamela Maher David Schubert
author_sort	Joshua Goldberg
title	Targeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities
title_short	Targeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities
title_full	Targeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities
title_fullStr	Targeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities
title_full_unstemmed	Targeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities
title_sort	targeting of intracellular ca2+ stores as a therapeutic strategy against age-related neurotoxicities
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/aab8f71534334401ab0fe2d1f969c108
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Targeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities

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