Parkinson’s Disease: Calcium Dysregulation as a Multilevel Mechanism of Selective Neuronal Vulnerability, with Implications for Therapeutic Strategy

Main Article Content

Weijie Lai
ZJU-UoE Institute, Zhejiang University, Haining, China

DOI: https://doi.org/10.70267/lshe.20260116

Keywords

Parkinson’s disease, calcium dysregulation, selective neuronal vulnerability, dopaminergic neurons, α-synuclein pathology

Abstract

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterised by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. Despite extensive investigation into genetic and environmental risk factors, the mechanisms underlying this selective neuronal vulnerability remain incompletely understood. Increasing evidence suggests that calcium dysregulation represents a unifying pathogenic mechanism linking molecular, cellular, and systems-level processes in PD. This review synthesises evidence demonstrating how the intrinsic reliance of substantia nigra dopaminergic neurons on calcium-dependent autonomous pacemaking imposes a sustained metabolic burden that predisposes these neurons to degeneration. It examines how genetically diverse PD-associated mutations, including those affecting PINK1/Parkin, LRRK2, and GBA, converge on disrupted calcium homeostasis through distinct cellular pathways involving mitochondrial buffering, lysosomal calcium signalling, and organelle quality control. At the cellular level, chronic calcium dysregulation drives oxidative stress, α-synuclein aggregation, and impaired autophagy, forming a self-reinforcing cycle of neuronal dysfunction. These processes extend beyond individual neurons, promoting neuroinflammation and basal ganglia circuit reorganisation that ultimately underlie motor symptom expression. The review further discusses the therapeutic implications of this multilevel framework, highlighting why broad calcium channel blockade has shown limited clinical efficacy. It argues that future disease-modifying strategies will require greater molecular and temporal precision, as well as integration with systems-level neuromodulation approaches that reduce activity-dependent calcium and metabolic burden. Overall, calcium dysregulation emerges as a central integrator of vulnerability across biological scales in Parkinson’s disease, offering a coherent framework for understanding pathogenesis and guiding therapeutic innovation.

Abstract 20 | PDF Downloads 8

References

  • [1] Bloem, B. R., Okun, M. S. and Klein, C. Parkinson’s disease. Lancet. 2021, 397(10291), pp. 2284-2303. https://doi.org/10.1016/s0140-6736(21)00218-x.
  • [2] Ben-Shlomo, Y., Darweesh, S., Llibre-Guerra, J., Marras, C., San Luciano, M. and Tanner, C. The epidemiology of Parkinson’s disease. Lancet. 2024, 403(10423), pp. 283-292. https://doi.org/10.1016/s0140-6736(23)01419-8.
  • [3] Michel, P. P., Hirsch, E. C. and Hunot, S. Understanding Dopaminergic Cell Death Pathways in Parkinson Disease. Neuron. 2016, 90(4), pp. 675-91. https://doi.org/10.1016/j.neuron.2016.03.038.
  • [4] Verma, A. and Ravindranath, V. Ca(V)1.3 L-Type Calcium Channels Increase the Vulnerability of Substantia Nigra Dopaminergic Neurons in MPTP Mouse Model of Parkinson’s Disease. Frontiers in Aging Neuroscience. 2019, 11, p. 382. https://doi.org/10.3389/fnagi.2019.00382.
  • [5] Filimontseva, A., Fu, Y., Vila, M. and Halliday, G. M. Neuromelanin and selective neuronal vulnerability to Parkinson’s disease. Trends in Neurosciences. 2025, 48(6), pp. 445-459. https://doi.org/10.1016/j.tins.2025.04.005.
  • [6] Benkert, J., Hess, S., Roy, S., Beccano-Kelly, D., Wiederspohn, N., Duda, J., Simons, C., Patil, K., Gaifullina, A., Mannal, N., et al. Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease. Nature Communications. 2019, 10(1), p. 5094. https://doi.org/10.1038/s41467-019-12834-x.
  • [7] Beccano-Kelly, D. A., Cherubini, M., Mousba, Y., Cramb, K. M. L., Giussani, S., Caiazza, M. C., Rai, P., Vingill, S., Bengoa-Vergniory, N., Ng, B., et al. Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons. iScience. 2023, 26(7), p. 107044. https://doi.org/10.1016/j.isci.2023.107044.
  • [8] Lin, J., Pang, D., Li, C., Ou, R., Yu, Y., Cui, Y., Huang, J. and Shang, H. Calcium channel blockers and Parkinson’s disease: a systematic review and meta-analysis. Therapeutic Advances in Neurological Disorders. 2024, 17, p. 17562864241252713. https://doi.org/10.1177/17562864241252713.
  • [9] Guzman, J. N., Sánchez-Padilla, J., Chan, C. S. and Surmeier, D. J. Robust pacemaking in substantia nigra dopaminergic neurons. Journal of Neuroscience. 2009, 29(35), pp. 11011-9. https://doi.org/10.1523/jneurosci.2519-09.2009.
  • [10] Guzman, J. N., Sanchez-Padilla, J., Wokosin, D., Kondapalli, J., Ilijic, E., Schumacker, P. T. and Surmeier, D. J. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature. 2010, 468(7324), pp. 696-700. https://doi.org/10.1038/nature09536.
  • [11] Surmeier, D. J., Guzman, J. N., Sanchez-Padilla, J. and Schumacker, P. T. The role of calcium and mitochondrial oxidant stress in the loss of substantia nigra pars compacta dopaminergic neurons in Parkinson’s disease. Neuroscience. 2011, 198, pp. 221-31. https://doi.org/10.1016/j.neuroscience.2011.08.045.
  • [12] Zucca, F. A., Segura-Aguilar, J., Ferrari, E., Muñoz, P., Paris, I., Sulzer, D., Sarna, T., Casella, L. and Zecca, L. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Progress in Neurobiology. 2017, 155, pp. 96-119. https://doi.org/10.1016/j.pneurobio.2015.09.012.
  • [13] Zhou, Z. D., Yi, L. X., Wang, D. Q., Lim, T. M. and Tan, E. K. Role of dopamine in the pathophysiology of Parkinson’s disease. Translational Neurodegeneration. 2023, 12(1), p. 44. https://doi.org/10.1186/s40035-023-00378-6.
  • [14] Dryanovski, D. I., Guzman, J. N., Xie, Z., Galteri, D. J., Volpicelli-Daley, L. A., Lee, V. M., Miller, R. J., Schumacker, P. T. and Surmeier, D. J. Calcium entry and α-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. Journal of Neuroscience. 2013, 33(24), pp. 10154-64. https://doi.org/10.1523/jneurosci.5311-12.2013.
  • [15] Ricke, K. M., Paß, T., Kimoloi, S., Fährmann, K., Jüngst, C., Schauss, A., Baris, O. R., Aradjanski, M., Trifunovic, A., Eriksson Faelker, T. M., et al. Mitochondrial Dysfunction Combined with High Calcium Load Leads to Impaired Antioxidant Defense Underlying the Selective Loss of Nigral Dopaminergic Neurons. Journal of Neuroscience. 2020, 40(9), pp. 1975-1986. https://doi.org/10.1523/jneurosci.1345-19.2019.
  • [16] Verkhratsky, A. Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiological Reviews. 2005, 85(1), pp. 201-79. https://doi.org/10.1152/physrev.00004.2004.
  • [17] Matuz-Mares, D., González-Andrade, M., Araiza-Villanueva, M. G., Vilchis-Landeros, M. M. and Vázquez-Meza, H. Mitochondrial calcium: Effects of its imbalance in disease. Antioxidants (Basel). 2022, 11(5), p. 801. https://doi.org/10.3390/antiox11050801.
  • [18] Gandhi, S., Wood-Kaczmar, A., Yao, Z., Plun-Favreau, H., Deas, E., Klupsch, K., Downward, J., Latchman, D. S., Tabrizi, S. J., Wood, N. W., et al. PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Molecular Cell. 2009, 33(5), pp. 627-38. https://doi.org/10.1016/j.molcel.2009.02.013.
  • [19] Dong-Chen, X., Yong, C., Yang, X., Chen-Yu, S. and Li-Hua, P. Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions. Signal Transduction and Targeted Therapy. 2023, 8(1), p. 73. https://doi.org/10.1038/s41392-023-01353-3.
  • [20] Chiasserini, D., Paciotti, S., Eusebi, P., Persichetti, E., Tasegian, A., Kurzawa-Akanbi, M., Chinnery, P. F., Morris, C. M., Calabresi, P., Parnetti, L., et al. Selective loss of glucocerebrosidase activity in sporadic Parkinson’s disease and dementia with Lewy bodies. Molecular Neurodegeneration. 2015, 10, p. 15. https://doi.org/10.1186/s13024-015-0010-2.
  • [21] Barazzuol, L., Giamogante, F., Brini, M. and Calì, T. PINK1/Parkin mediated mitophagy, Ca2+ signalling, and ER-mitochondria contacts in Parkinson’s disease. International Journal of Molecular Sciences. 2020, 21(5), p. 1772. https://doi.org/10.3390/ijms21051772.
  • [22] Gregori, M., Pereira, G. J. S., Allen, R., West, N., Chau, K. Y., Cai, X., Bostock, M. P., Bolsover, S. R., Keller, M., Lee, C. Y., et al. Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson’s disease. Journal of Cell Biology. 2025, 224(6), p. e202412055. https://doi.org/10.1083/jcb.202412055.
  • [23] Xiong, Y. and Yu, J. LRRK2 in Parkinson’s disease: upstream regulation and therapeutic targeting. Trends in Molecular Medicine. 2024, 30(10), pp. 982-996. https://doi.org/10.1016/j.molmed.2024.07.003.
  • [24] Alharbi, A. F. and Parrington, J. TPC2 in drug development: Emerging target for cancer, viral infections, cardiovascular diseases, and neurological disorders. Pharmacological Research. 2025, 213, p. 107655. https://doi.org/10.1016/j.phrs.2025.107655.
  • [25] Medina, D. L., Di Paola, S., Peluso, I., Armani, A., De Stefani, D., Venditti, R., Montefusco, S., Scotto-Rosato, A., Prezioso, C., Forrester, A., et al. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nature Cell Biology. 2015, 17(3), pp. 288-99. https://doi.org/10.1038/ncb3114.
  • [26] Burbulla, L. F. and Krainc, D. The role of dopamine in the pathogenesis of GBA1-linked Parkinson’s disease. Neurobiology of Disease. 2019, 132, p. 104545. https://doi.org/10.1016/j.nbd.2019.104545.
  • [27] Giamogante, F., Barazzuol, L., Maiorca, F., Poggio, E., Esposito, A., Masato, A., Napolitano, G., Vagnoni, A., Calì, T. and Brini, M. A SPLICS reporter reveals [Formula: see text]-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation. Nature Communications. 2024, 15(1), p. 1516. https://doi.org/10.1038/s41467-024-46007-2.
  • [28] Kaur, S., Sehrawat, A., Mastana, S. S., Kandimalla, R., Sharma, P. K., Bhatti, G. K. and Bhatti, J. S. Targeting calcium homeostasis and impaired inter-organelle crosstalk as a potential therapeutic approach in Parkinson’s disease. Life Sciences. 2023, 330, p. 121995. https://doi.org/10.1016/j.lfs.2023.121995.
  • [29] Filadi, R., Theurey, P. and Pizzo, P. The endoplasmic reticulum-mitochondria coupling in health and disease: Molecules, functions and significance. Cell Calcium. 2017, 62, pp. 1-15. https://doi.org/10.1016/j.ceca.2017.01.003.
  • [30] Ramezani, M., Wagenknecht-Wiesner, A., Wang, T., Holowka, D. A., Eliezer, D. and Baird, B. A. Alpha synuclein modulates mitochondrial Ca2+ uptake from ER during cell stimulation and under stress conditions. NPJ Parkinsons Dis. 2023, 9(1), p. 137. https://doi.org/10.1038/s41531-023-00578-x.
  • [31] Bellomo, G., Paciotti, S., Gatticchi, L. and Parnetti, L. The vicious cycle between α-synuclein aggregation and autophagic-lysosomal dysfunction. Movement Disorders. 2020, 35(1), pp. 34-44. https://doi.org/10.1002/mds.27895.
  • [32] Lang, M., Pramstaller, P. P. and Pichler, I. Crosstalk of organelles in Parkinson’s disease - MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes. Molecular Neurodegeneration. 2022, 17(1), p. 50. https://doi.org/10.1186/s13024-022-00555-7.
  • [33] Bastioli, G., Piccirillo, S., Graciotti, L., Carone, M., Sprega, G., Taoussi, O., Preziuso, A. and Castaldo, P. Calcium deregulation in neurodegeneration and neuroinflammation in Parkinson’s disease: Role of calcium-storing organelles and sodium-calcium exchanger. Cells. 2024, 13(15), p. 1301. https://doi.org/10.3390/cells13151301.
  • [34] Chung, Y. C., Shin, W. H., Baek, J. Y., Cho, E. J., Baik, H. H., Kim, S. R., Won, S. Y. and Jin, B. K. CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease. Experimental and Molecular Medicine. 2016, 48(1), p. e205. https://doi.org/10.1038/emm.2015.100.
  • [35] Ruan, Z., Zhang, D., Huang, R., Sun, W., Hou, L., Zhao, J. and Wang, Q. Microglial activation damages dopaminergic neurons through mmp-2/-9-mediated increase of blood-brain barrier permeability in a Parkinson’s disease mouse model. International Journal of Molecular Sciences. 2022, 23(5), p. 2793. https://doi.org/10.3390/ijms23052793.
  • [36] Rommelfanger, K. S. and Wichmann, T. Extrastriatal dopaminergic circuits of the Basal Ganglia. Frontiers in Neuroanatomy. 2010, 4, p. 139. https://doi.org/10.3389/fnana.2010.00139.
  • [37] McGregor, M. M. and Nelson, A. B. Circuit mechanisms of Parkinson’s disease. Neuron. 2019, 101(6), pp. 1042-1056. https://doi.org/10.1016/j.neuron.2019.03.004.
  • [38] Cazorla, M., Kang, U. J. and Kellendonk, C. Balancing the basal ganglia circuitry: a possible new role for dopamine D2 receptors in health and disease. Movement Disorders. 2015, 30(7), pp. 895-903. https://doi.org/10.1002/mds.26282.
  • [39] Ellens, D. J. and Leventhal, D. K. Review: electrophysiology of basal ganglia and cortex in models of Parkinson disease. Journal of Parkinson’s Disease. 2013, 3(3), pp. 241-54. https://doi.org/10.3233/jpd-130204.
  • [40] Galvan, A., Devergnas, A. and Wichmann, T. Alterations in neuronal activity in basal ganglia-thalamocortical circuits in the parkinsonian state. Frontiers in Neuroanatomy. 2015, 9, p. 5. https://doi.org/10.3389/fnana.2015.00005.
  • [41] Stoessl, A. J., Lehericy, S. and Strafella, A. P. Imaging insights into basal ganglia function, Parkinson’s disease, and dystonia. Lancet. 2014, 384(9942), pp. 532-44. https://doi.org/10.1016/s0140-6736(14)60041-6.
  • [42] Surmeier, D. J., Halliday, G. M. and Simuni, T. Calcium, mitochondrial dysfunction and slowing the progression of Parkinson’s disease. Experimental Neurology. 2017, 298(Pt B), pp. 202-209. https://doi.org/10.1016/j.expneurol.2017.08.001.
  • [43] Swart, T. and Hurley, M. J. Calcium channel antagonists as disease-modifying therapy for Parkinson’s disease: Therapeutic rationale and current status. CNS Drugs. 2016, 30(12), pp. 1127-1135. https://doi.org/10.1007/s40263-016-0393-9.
  • [44] Caulfield, M. E., Manfredsson, F. P. and Steece-Collier, K. The role of striatal Cav1.3 calcium channels in therapeutics for Parkinson’s disease. Handbook of Experimental Pharmacology. 2023, 279, pp. 107-137. https://doi.org/10.1007/164_2022_629.
  • [45] Vijiaratnam, N., Simuni, T., Bandmann, O., Morris, H. R. and Foltynie, T. Progress towards therapies for disease modification in Parkinson’s disease. Lancet Neurology. 2021, 20(7), pp. 559-572. https://doi.org/10.1016/s1474-4422(21)00061-2.
  • [46] Liss, B. and Striessnig, J. The potential of L-type calcium channels as a drug target for neuroprotective therapy in Parkinson’s disease. Annual Review of Pharmacology and Toxicology. 2019, 59, pp. 263-289. https://doi.org/10.1146/annurev-pharmtox-010818-021214.
  • [47] Duda, J., Pötschke, C. and Liss, B. Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson’s disease. Journal of Neurochemistry. 2016, 139 Suppl 1(Suppl Suppl 1), pp. 156-178. https://doi.org/10.1111/jnc.13572.
  • [48] Habets, J. G. V., Heijmans, M., Kuijf, M. L., Janssen, M. L. F., Temel, Y. and Kubben, P. L. An update on adaptive deep brain stimulation in Parkinson’s disease. Movement Disorders. 2018, 33(12), pp. 1834-1843. https://doi.org/10.1002/mds.115.
  • [49] Chen, D., Zhao, Z., Shi, J., Li, S., Xu, X., Wu, Z., Tang, Y., Liu, N., Zhou, W., Ni, C., et al. Harnessing the sensing and stimulation function of deep brain-machine interfaces: a new dawn for overcoming substance use disorders. Transl Psychiatry. 2024, 14(1), p. 440. https://doi.org/10.1038/s41398-024-03156-8.
  • [50] Mao, Z., Ling, Z., Pan, L., Xu, X., Cui, Z., Liang, S. and Yu, X. Comparison of efficacy of deep brain stimulation of different targets in Parkinson’s disease: A network meta-analysis. Frontiers in Aging Neuroscience. 2019, 11, p. 23. https://doi.org/10.3389/fnagi.2019.00023.
  • [51] Porta, M., Servello, D., Zekaj, E., Gonzalez-Escamilla, G. and Groppa, S. Pre-dopa deep brain stimulation: Is early deep brain stimulation able to modify the natural course of Parkinson’s disease? Frontiers in Neuroscience. 2020, 14, p. 492. https://doi.org/10.3389/fnins.2020.00492.
  • [52] Limousin, P. and Foltynie, T. Long-term outcomes of deep brain stimulation in Parkinson disease. Nature Reviews: Neurology. 2019, 15(4), pp. 234-242. https://doi.org/10.1038/s41582-019-0145-9.
  • [53] Wang, S., Zhu, G., Shi, L., Zhang, C., Wu, B., Yang, A., Meng, F., Jiang, Y. and Zhang, J. Closed-loop adaptive deep brain stimulation in Parkinson’s disease: Procedures to achieve it and future perspectives. Journal of Parkinson’s Disease. 2023, 13(4), pp. 453-471. https://doi.org/10.3233/jpd-225053.
  • [54] Johnson, L. A., Nebeck, S. D., Muralidharan, A., Johnson, M. D., Baker, K. B. and Vitek, J. L. Closed-Loop Deep Brain Stimulation Effects on Parkinsonian Motor Symptoms in a Non-Human Primate - Is Beta Enough? Brain Stimulation. 2016, 9(6), pp. 892-896. https://doi.org/10.1016/j.brs.2016.06.051.
  • [55] Parastarfeizabadi, M. and Kouzani, A. Z. Advances in closed-loop deep brain stimulation devices. Journal of Neuroengineering and Rehabilitation. 2017, 14(1), p. 79. https://doi.org/10.1186/s12984-017-0295-1.
  • [56] Rosa, M., Arlotti, M., Ardolino, G., Cogiamanian, F., Marceglia, S., Di Fonzo, A., Cortese, F., Rampini, P. M. and Priori, A. Adaptive deep brain stimulation in a freely moving Parkinsonian patient. Movement Disorders. 2015, 30(7), pp. 1003-5. https://doi.org/10.1002/mds.26241.

Article Sidebar

PDF
Published
Mar 27, 2026
Conference Proceedings Volume
Vol. 12 (2026): Proceedings of the 2026 International Conference on Life Sciences and Health Engineering (IC-LSHE 2026)
Section
Articles
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

How to Cite

Lai, Weijie. “Parkinson’s Disease: Calcium Dysregulation As a Multilevel Mechanism of Selective Neuronal Vulnerability, With Implications for Therapeutic Strategy”. Exploring Science Academic Conference Series, vol. 12, Mar. 2026, pp. 136-4, https://doi.org/10.70267/lshe.20260116.