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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 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 ?-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.

SUBMITTER: Goldberg J

PROVIDER: S-EPMC7445274 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Targeting of intracellular Ca<sup>2+</sup> stores as a therapeutic strategy against age-related neurotoxicities.

Goldberg Joshua J Currais Antonio A Ates Gamze G Huang Ling L Shokhirev Maxim M Maher Pamela P Schubert David D

NPJ aging and mechanisms of disease 20200824

Calcium dysregulation often underlies pathologies associated with aging and age-associated neurodegenerative diseases. Cells express a unique pattern of Ca<sup>2+</sup> 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 medi ...[more]

PMID: 32884834

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Project description:Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) increase myofilament Ca2+ sensitivity. Mouse models exhibit increased Ca2+ buffering and arrhythmias, and we hypothesized that these changes are primary effects of the mutations (independent of compensatory changes) and that increased Ca2+ buffering and altered Ca2+ handling contribute to HCM pathogenesis via activation of Ca2+-dependent signaling. Here, we determined the primary effects of HCM mutations on intracellular Ca2+ handling and Ca2+-dependent signaling in a model system possessing Ca2+-handling mechanisms and contractile protein isoforms closely mirroring the human environment in the absence of potentially confounding remodeling. Using adenovirus, we expressed HCM-causing variants of human troponin-T, troponin-I, and α-tropomyosin (R92Q, R145G, and D175N, respectively) in isolated guinea pig left ventricular cardiomyocytes. After 48 h, each variant had localized to the I-band and comprised ∼50% of the total protein. HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes. We observed increased diastolic [Ca2+] and slowed Ca2+ reuptake, coupled with a significant decrease in basal sarcomere length and slowed relaxation. HCM mutant cells had higher sodium/calcium exchanger activity, sarcoplasmic reticulum Ca2+ load, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity driven by Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of phospholamban. The ryanodine receptor (RyR) leak/load relationship was also increased, driven by CaMKII-mediated RyR phosphorylation. Altered Ca2+ homeostasis also increased signaling via both calcineurin/NFAT and extracellular signal-regulated kinase pathways. Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM.

Dataset Information

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

Publications

Targeting of intracellular Ca<sup>2+</sup> stores as a therapeutic strategy against age-related neurotoxicities.

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Dataset Information

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

Publications

Targeting of intracellular Ca<sup>2+</sup> stores as a therapeutic strategy against age-related neurotoxicities.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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