Role of Calcium Signaling in the Pathogenesis of Neurodegenerative Diseases

D. Panayotova; Z. Kokanova-Nedyalkova; M. Kondeva-Burdina

doi:10.2478/amb-2026-0064

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Role of Calcium Signaling in the Pathogenesis of Neurodegenerative Diseases

Acta Medica Bulgarica

Volume 53 (2026): Issue 2 (June 2026)

By: D. Panayotova, Z. Kokanova-Nedyalkova and M. Kondeva-Burdina

Open Access

|Jun 2026

Abstract

Calcium (Ca²+) is a central intracellular second messenger regulating cellular homeostasis through tightly controlled signaling. Intracellular Ca²+ dynamics depend on coordinated interactions between the endoplasmic reticulum (ER), mitochondria, and plasma membrane channels, including SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca²+- ATPase, which is a calcium pump located in the sarcoplasmic and endoplasmic reticulum (SR and ER) pumps, inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), transient receptor potential (TRP) channels, and store-operated calcium entry (SOCE). ER–mitochondria contact sites integrate calcium signaling with mitochondrial energetics, oxidative stress responses, autophagy, and apoptosis. Changes in calcium signaling play a key role as a risk factor in the pathogenesis of neurodegenerative diseases, with calcium influx pathways, including store-operated calcium entry (SOCE), critically implicated in their pathophysiology. Despite ongoing research, these diseases remain incurable, and current therapies provide only symptomatic relief. Restoration of calcium signaling homeostasis is proposed as a potential therapeutic target for the treatment of neurodegenerative disorders. Proper functioning of calcium signaling pathways is critical for neuronal function. It has been clearly demonstrated that dysregulation of calcium signaling is a common feature of neurodegenerative diseases. Abnormal Ca²+ signaling leads to mitochondrial dysfunction and synaptic instability, and restoration of normal calcium homeostasis is a potential strategy for treating these diseases. SOCE impairment is observed in Alzheimer’s disease (AD), Huntington‘s disease (HD), and Parkinson‘s disease (PD). This review summarizes mechanistic insights into calcium signaling alterations involved in neurodegeneration, focusing on ER calcium storage, SERCA function, SOCE regulation, and calcium-dependent signaling pathways. Emerging neuroprotective strategies targeting calcium homeostasis, including pharmacological agents and natural bioactive compounds, are discussed. Restoration of intracellular Ca²+ balance represents a promising therapeutic approach to reduce calcium-mediated cytotoxicity and slow neurodegenerative progression.

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Articles in this issue

DOI: https://doi.org/10.2478/amb-2026-0064 | Journal eISSN: 2719-5384 | Journal ISSN: 0324-1750

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Language: English

Page range: 82 - 89

Submitted on: Aug 22, 2025

Accepted on: Oct 16, 2025

Published on: Jun 16, 2026

Published by: Medical University - Sofia

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

neurodegenerative diseases,

calcium signaling,

cellular homeostasis,

endoplasmic reticulum,

cell signaling,

apoptosis,

oxidative stress,

mitochondrial dysfunction,

Parkinson’s disease

Related subjects:

Medicine,

Basic medical science,

Immunology,

Clinical medicine,

Clinical medicine, other

© 2026 D. Panayotova, Z. Kokanova-Nedyalkova, M. Kondeva-Burdina, published by Medical University - Sofia
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Volume 53 (2026): Issue 2 (June 2026)