Role of calcium signaling in the pathogenesis of neurodegenerative diseases
DOI:
https://doi.org/10.2478/AMB-2026-0064Keywords:
neurodegenerative diseases, calcium signaling, cellular homeostasis, endoplasmic reticulum, cell signaling, apoptosis, oxidative stress, mitochondrial dysfunction, Parkinson‘s diseaseAbstract
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.
References
Szalai G, Krishnamurthy R, Hajnóczky G. Apoptosis driven by IP(3)-linked mitochondrial calcium signals. EMBO J, 1999;18(22):6349-6361. doi: 10.1093/emboj/18.22.6349.
Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science, 2003;300(5616): 135-139. doi: 10.1126/science.1081208.
Brini M, Calì T, Ottolini D, Carafoli E. Intracellular calcium homeostasis and signaling. Met Ions Life Sci, 2013;12:119168. doi: 10.1007/978-94-007-5561-1_5.
Bagur R, HajnóczkyG. Intracellular Ca2+ Sensing: Its role in calcium homeostasis and signaling. Mol Cell, 2017;66(6): 780-788. doi: 10.1016/j.molcel.2017.05.028.
Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signaling. Nat Rev Mol Cell Biol, 2000;1(1):11-21. doi: 10.1038/35036035.
Rizzuto R, Brini M, Murgia M, Pozzan T. Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science, 1993;262(5134):744747. doi: 10.1126/science.8235595.
Jouaville LS, Ichas F, Holmuhamedov EL, et al. Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes. Nature, 1995;377(6548):438-441. doi: 10.1038/377438a0.
Arnaudeau S, Kelley WL, Walsh Jr JV, Demaurex N. Mitochondria recycle Ca(2+) to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions. J Biol Chem, 2001;276(31):29430-29439. doi: 10.1074/jbc.M103274200.
Hajnóczky G, Robb-Gaspers LD, Seitz MB, Thomas AP. Decoding of cytosolic calcium oscillations in the mitochondria. Cell, 1995;82(3):415-424. doi: 10.1016/0092-8674(95)90430-1.
Pacher P, Hajnóczky G. Propagation of the apoptotic signal by mitochondrial waves. EMBO J, 2001;20(15):4107-4121. doi: 10.1093/emboj/20.15.4107.
Nakamura K, Bossy-Wetzel E, Burns K, et al. Changes in the endoplasmic reticulum luminal environment affect cell sensitivity to apoptosis. J Cell Biol, 2000;150(4): 731-740. doi: 10.1083/jcb.150.4.731.
Pinton P, Ferrarim D, Rapizzi E, et al. The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J, 2001;20(11): 26902701. doi: 10.1093/emboj/20.11.2690.
Arnaudeau S, Frieden M, Nakamura K, et al. Calreticulin differentially modulates calcium uptake and release in the endoplasmic reticulum and mitochondria. J Biol Chem, 2002;277(48):46696-46705. doi: 10.1074/jbc.M202395200.
Waring P. Redox active calcium ion channels and cell death. Arch Biochem Biophys, 2005;434(1):33-42. doi: 10.1016/j.abb.2004.08.001.
Federico M, Portiansky EL, Sommese L, et al. Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance. J Physiol, 2017;595(12):40894108.doi: 10.1113/JP273714.
Henke N, Albrecht P, Bouchachia I, et al. The plasma membrane channel ORAI1 mediates detrimental calcium influx caused by endogenous oxidative stress. Cell Death Dis, 2013;4(1):e470. doi: 10.1038/cddis.2012.216.
Sukumaran P, Da Conceicao VN, Sun Y, et al. Calcium signaling regulates autophagy and apoptosis. Cells, 2021;10(8):2125. doi: 10.3390/cells10082125.
Pchitskaya E, Popugaeva E, Bezprozvanny I. Calcium signaling and molecular mechanisms underlying neurodegenerative diseases. Cell Calcium, 2018;70:87-94. doi: 10.1016/j.ceca.2017.06.008.
Lu J, Wu M, Yue Z. Autophagy and Parkinson’s disease. Adv Exp Med Biol, 2020;1207:21-51. doi: 10.1007/978-981-15-4272-5_2.
Carafoli E. The ambivalent nature of the calcium signal. J Endocrinol Invest, 2004;27(6 Suppl):134-136.
Krols M, van Isterdael G, Asselbergh B, et al. Mitochondria-associated membranes as hubs for neurodegeneration. Acta Neuropathol, 2016;131(4):505-523. doi: 10.1007/s00401-015-1528-7.
Grossmann D, Malburg N, Glaß H, et al. Mitochondria-endoplasmic reticulum contact sites dynamics and calcium homeostasis are differentially disrupted in PINK1-PD or PRKN-PD neurons. Mov Disord, 2023;38(10):1822-1836. doi: 10.1002/mds.29525.
Zhang TQ, Li CC, Zhang TF, et al. Mechanism of astragaloside – alleviating PC12 cell injury by activating PI3K/AKT signaling pathway: based on network pharmacology and in vitro experiments. Zhongguo Zhong Yao Za Zhi, 2021;46(24):6465-6473. doi: 10.19540/j.cnki.cjcmm.20210902.702.
Cabezas R, El-Bachá RS, González J, et al. Mitochondrial functions in astrocytes: neuroprotective implications from oxidative damage by rotenone. Neurosci Res, 2012;74(2):8090. doi: 10.1016/j.neures.2012.07.008.
Salari AMN, Rasoulizadeh Z, Shabgah AG, et al. Exploring the mechanisms of kaempferol in neuroprotection: Implications for neurological disorders. Cell Biochem Funct, 2024;42(2):e3964. doi: 10.1002/cbf.3964.
Yuan YH, Yan WF, Sun JD, et al. The molecular mechanism of rotenone-induced α-synuclein aggregation: emphasizing the role of the calcium/GSK3β pathway. Toxicol Lett, 2015;233(2):163-171. doi: 10.1016/j.toxlet.2014.11.029.
Kang SY, Lee SB, Kim HJ, et al. Autophagic modulation by rosuvastatin prevents rotenone-induced neurotoxicity in an in vitro model of Parkinson‘s disease. Neurosci Lett, 2017;642:20-26. doi: 10.1016/j.neulet.2017.01.063.
Park BC, Lee YS, Park HJ, et al. Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death. Exp Mol Med, 2007;39(3):316-326. doi: 10.1038/emm.2007.35.
Wang J, Zhao J, Zhao K, et al. The role of calcium and iron homeostasis in Parkinson’s disease. Brain Sci, 2024;14(1):88. doi: 10.3390/brainsci14010088.
Ververis A, Ioannou K, Kyriakou S, et al. Sideritis scardica extracts demonstrate neuroprotective activity against Aβ25-35 Toxicity. Plants (Basel), 2023;12(8):1716. doi: 10.3390/plants12081716.
Lin X, Liang Y, Herrera-Molina R, Montag D. Neuroplastin in neuropsychiatric Diseases. Genes (Basel), 2021;12(10):1507. doi: 10.3390/genes12101507.
Levin J, Maaß S, Schuberth M, et al; PROMESA Study Group. Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial. Lancet Neurol, 2019;18(8):724-735. doi: 10.1016/S1474-4422(19)30141-3.
Ververis A, Savvidou G, Ioannou K, et al. Greek sage exhibits neuroprotective activity against amyloid beta-induced toxicity. Evid Based Complement Alternat Med, 2020;2020:2975284. doi: 10.1155/2020/2975284.
Mori T, Koyama N, Tan J, et al. Combined treatment with the phenolics (-)-epigallocatechin-3-gallate and ferulic acid improves cognition and reduces Alzheimer-like pathology in mice. J Biol Chem, 2019;294(8):2714-2731. doi: 10.1074/jbc.RA118.004280.
Klocke B, Krone K, Tornes J, et al. Insights into the role of intracellular calcium signaling in the neurobiology of neurodevelopmental disorders. Front Neurosci, 2023;17:1093099. doi: 10.3389/fnins.2023.1093099.
Britzolaki A, Saurine J, Flaherty E, et al. The SERCA2: A gatekeeper of neuronal calcium homeostasis in the brain. Cell Mol Neurobiol, 2018;38(5):981-994. doi: 10.1007/s10571-018-0583-8.
Britzolaki A, Saurine J, Klocke B, Pitychoutis PM. A Role for SERCA pumps in the neurobiology of neuropsychiatric and neurodegenerative disorders. Adv Exp Med Biol, 2020;1131: 131-161. doi: 10.1007/978-3-030-12457-1_6.
Viskupicova J, Rezbarikova P. Natural polyphenols as SERCA activators: role in the endoplasmic reticulum stress-related diseases. Molecules, 2022;27(16):5095. doi: 10.3390/molecules27165095.
La Rovere RML, Roest G, Bultynck G, Parys JB. Intracellular Ca(2+) signaling and Ca(2+) microdomains in the control of cell survival, apoptosis and autophagy. Cell Calcium, 2016;60(2):74-87. doi: 10.1016/j.ceca.2016.04.005.
Enders M, Heider T, Ludwig A, Kuerten S. Strategies for neuroprotection in multiple sclerosis and the role of calcium. Int J Mol Sci, 2020;21(5):1663. doi: 10.3390/ijms21051663.
Zündorf G, Reiser G. Calcium dysregulation and homeostasis of neural calcium in the molecular mechanisms of neurodegenerative diseases provide multiple targets for neuroprotection. Antioxid Redox Signal, 2011;14(7):1275-1288. doi: 10.1089/ars.2010.3359.
Subramaniam SR, Chesselet MF. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol, 2013;106-107:17-32. doi: 10.1016/j.pneurobio.2013.04.004.
Rzajew J, Radzik T, Rebas E. Calcium-involved action of phytochemicals: carotenoids and monoterpenes in the brain. Int J Mol Sci, 2020;21(4):1428. doi: 10.3390/ijms21041428.
Garcia-Martinez EM, Sanz-Blasco S, Karachitos A, et al. Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells. Biochem Pharmacol, 2010;79(2):239-250. doi: 10.1016/j.bcp.2009.07.028.
Gao X, Yang X, Zhang B. Neuroprotection of taurine against bilirubin-induced elevation of apoptosis and intracellular free calcium ion in vivo. Toxicol Mech Methods, 2011;21(5):383387. doi: 10.3109/15376516.2010.546815.
Sun A, Xu X, Lin J, et al. Neuroprotection by saponins. Phytother Res, 2015;29(2):187-200. doi: 10.1002/ptr.5246.
Wu Y, Kazumura K, Maruyama W, et al. Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection. J Neural Transm (Vienna), 2015;122(10):1399-1407. doi: 10.1007/s00702-015-1398-0.
Federico M, Portiansky EL, Sommese L, et al. Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance. J Physiol, 2017;595(12):40894108. doi: 10.1113/JP273714.
Sánchez JC, López-Zapata DF, Romero-Leguizamón CR. Calcium transport mechanisms in neuroprotection and neurotoxicity. Rev Neurol, 2010;51(10):624-632.
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