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

Joshua Goldberg,Gamze Ates,Ling Huang,Pamela Maher,Maxim Shokhirev,David Schubert,Antonio Currais

doi:10.1038/s41514-020-00048-1

Joshua Goldberg, Gamze Ates + Show 5 more

Open Access

https://doi.org/10.1038/s41514-020-00048-1

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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.

Highlights

Calcium ions (Ca2+) impact most aspects of cell behavior and metabolism and their aberrant regulation is often associated with aging, Alzheimer’s disease (AD), and neurotoxicity[1,2]
Changes in hippocampal gene expression were examined between 9-month-old control mice and 13-month-old mice fed either control diet or J147 for 4 months starting at 9 months of age, a treatment that suppresses the aging phenotype[12]
Because our screening platform is based in part upon calcium dysregulation, we used gene set enrichment analysis (GSEA) to ask how J147 affected age-associated changes corresponding to Ca2+-related ion channels and transporters

Summary

Introduction

Calcium ions (Ca2+) impact most aspects of cell behavior and metabolism and their aberrant regulation is often associated with aging, Alzheimer’s disease (AD), and neurotoxicity[1,2]. The intracellular Ca2+ concentration ([Ca2+]) varies depending on its subcellular location and the maintenance of these Ca2+ stores is critical for the propagation of inter-organelle Ca2+ signals, such as those driving mitochondrial oxidative metabolism[3] and the initiation of ER stress responses[4]. A treatment to alleviate this form of acute, Ca2+-dependent toxicity would have significant therapeutic value. The AD drug candidate J147 was identified using a phenotypic screening platform designed to select drug candidates that protect against toxicities associated with brain aging, some of which involve dysregulated Ca2+ homeostasis[6]. The molecular target of J147 is the α-F1 mitochondrial ATP synthase (ATP5A)[11], a central player in Ca2+ metabolism that can drive Ca2+ flux via changes in the ATP-generated H+ gradient or opening of the mitochondrial permeability transition pore (mPTP)

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