Calcineurin/NFAT signaling in the temporal integration of Ca²⁺ stress in neurodegeneration.

Authors

Bruna Da Silva Oliveira, Metello Innocenti, Francesca Granucci

Published in

Cell death discovery. Jul 11, 2026. Epub Jul 11, 2026.

Abstract

The calcineurin (CaN)/nuclear factor of activated T cells (NFAT) signalling axis is a Ca²⁺-responsive pathway that translates intracellular Ca²⁺ signals into long-term transcriptional programmes. Chronic disruption of intracellular Ca²⁺ homoeostasis is a convergent feature of neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). In these conditions, sustained or repetitive Ca²⁺ elevations promote prolonged activation of the CaN/NFAT pathway, thereby linking Ca²⁺ dysregulation to persistent cellular responses. In this review, we summarise the molecular organisation and regulation of the Ca²⁺/CaN/NFAT pathway and discuss its physiological roles in neurons and glial cells, including synaptic plasticity, neurodevelopment, neurogenesis, and neuroinflammatory responses. We critically examine experimental evidence linking CaN/NFAT signalling to AD and PD, distinguishing direct mechanistic roles from associative and model-dependent findings. Across disease contexts, the CaN/NFAT axis appears to function as a molecular node at which diverse insults, including amyloid-β and tau aggregates, α-synuclein toxicity, mitochondrial dysfunction, and chronic inflammatory cues, converge under conditions of sustained Ca²⁺ dysregulation. We propose that the pathological relevance of CaN/NFAT lies less in pathway activation per se than in its capacity to convert chronic Ca²⁺-dependent stress signals into persistent transcriptional states affecting synaptic integrity, inflammatory tone, and cellular resilience. We conclude by discussing current therapeutic strategies targeting this pathway, their limitations, and the need for temporally and cell-type-specific modulation.

PMID:
42436132
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.

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