Role of Calcium Signaling in the Pathogenesis of Neurodegenerative Diseases
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, Cali T, Ottolini D, Carafoli E. Intracellular calcium homeostasis and signaling. Met Ions Life Sci, 2013, 12: 119-168. 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): 744-747. doi: 10.1126/science.8235595.
- Jouaville LS, Ichas F, Holmuhamedov EL, et al. Synchronization of calcium waves by mitochondrial substrates in Xeno- pus laevis oocytes. Nature, 1995, 377(6548): 438-441. doi: 10.1038/377438a0.
- Arnaudeau S, Kelley WL, Walsh Jr JV, Demaurex N. Mito-chondria 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): 2690-2701. 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): 4089-4108.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, GlalB 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-Bachd RS, Gonzalez J, et al. Mitochondrial functions in astrocytes: neuroprotective implications from oxidative damage by rotenone. Neurosci Res, 2012, 74(2): 80-90. 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 a-synuclein aggregation: emphasizing the role of the calcium/GSK3p 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-hydroxydopa- mine-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, loannou K, Kyriakou S, et al. Sideritis scardica extracts demonstrate neuroprotective activity against A025-35 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, MaaH 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, loannou K, et al. Greek sage exhibits neuroprotective activity against amyloid beta-induced toxicity. Evid Based Complement Alternat Med, 2020, 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, Tomes J, et al. Insights into the role of intracellular calcium signaling in the neurobiology of neuro-developmental disorders. Front Neurosci, 2023, 17: 1093099.
- Britzolaki A, Saurine J, Flaherty E, et al. The SERCA2: Agatekeeper 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.
- Gaydarski L, Petrova K, Georgiev GP, et al. CD44 Expression Dynamics in the Corpus Callosum After Cuprizone-lnduced Demyelination. Acta Medica Bulgarica, (2026) 53(s1), 46-51. https://doi.org/10.2478/amb-2026-0006
- 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.
- 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): 383-387. 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.
- WO 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.
- 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): 4089-4108.
- Sánchez JC, López-Zapata DF, Romero-Leguizamón CR. Calcium transport mechanisms in neuroprotection and neurotoxicity. Rev Neurol, 2010, 51(10): 624-632.
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:
Related subjects:
© 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.