Parkinson’s disease is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the Substantia Nigra Pars Compacta, located in the midbrain. Neurons in the SNc project extensively into the striatum, comprising the caudate and putamen, where dopamine regulates the activity of basal ganglia circuits involved in motor control and learning. While the cardinal motor symptoms of PD have long been attributed to dopaminergic loss, recent studies reveal that PD pathology is more complex. Understanding these mechanisms not only explains the disease’s diverse symptoms but also offers novel strategies for intervention. This essay examines the multifactorial pathophysiology of PD, focusing on clinical symptoms, basal ganglia circuitry, the vulnerability of dopaminergic neurons, associated genes, and the role of other neurotransmitters. It also discusses stem cell therapies and future directions for treatment, aiming to provide a comprehensive understanding of Parkinson’s disease.
References
[1]
Basal Ganglia and Parkinson’s Disease: How Are They Connected? (n.d.) NeuroLab 360. https://www.neurolab360.com/blog/basalgangliaandpd
[2]
Harris, J.P., Burrell, J.C., Struzyna, L.A., Chen, H.I., Serruya, M.D., Wolf, J.A., et al. (2020) Emerging Regenerative Medicine and Tissue Engineering Strategies for Parkinson’s Disease. NPJParkinson’sDisease, 6, Article No. 4. https://doi.org/10.1038/s41531-019-0105-5
[3]
Young, C.B., Sonne, J. and Reddy, V. (2023) Neuroanatomy, Basal Ganglia. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK537141/
[4]
Rocha, G.S., Freire, M.A.M., Britto, A.M., Paiva, K.M., Oliveira, R.F., Fonseca, I.A.T., et al. (2023) Basal Ganglia for Beginners: The Basic Concepts You Need to Know and Their Role in Movement Control. FrontiersinSystemsNeuroscience, 17, Article ID: 1242929. https://doi.org/10.3389/fnsys.2023.1242929
[5]
Mingo, Y.B., Escobar Galvis, M.L. and Henderson, M.X. (2025) α-Synuclein Pathology and Mitochondrial Dysfunction: Toxic Partners in Parkinson’s Disease. NeurobiologyofDisease, 209, Article ID: 106889. https://doi.org/10.1016/j.nbd.2025.106889
Ni, A. and Ernst, C. (2022) Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active. FrontiersinCellularNeuroscience, 16, Article ID: 826193. https://doi.org/10.3389/fncel.2022.826193
[8]
Zhou, Z.D., Yi, L.X., Wang, D.Q., Lim, T.M. and Tan, E.K. (2023) Role of Dopamine in the Pathophysiology of Parkinson’s Disease. TranslationalNeurodegeneration, 12, Article No. 44. https://doi.org/10.1186/s40035-023-00378-6
[9]
Xu, J., Minobe, E. and Kameyama, M. (2022) Ca2+ Dyshomeostasis Links Risk Factors to Neurodegeneration in Parkinson’s Disease. FrontiersinCellularNeuroscience, 16, Article ID: 867385. https://doi.org/10.3389/fncel.2022.867385
[10]
Phan, L., Miller, D., Gopinath, A., Lin, M., Miller, E.J., Guenther, D., et al. (2025) Parkinson’s Paradox: Alpha-Synuclein’s Selective Strike on SNc Dopamine Neurons over VTA. NPJParkinson’sDisease, 11, Article No. 207. https://doi.org/10.1038/s41531-025-01055-3
[11]
Blauwendraat, C., Nalls, M.A. and Singleton, A.B. (2020) The Genetic Architecture of Parkinson’s Disease. TheLancetNeurology, 19, 170-178. https://doi.org/10.1016/s1474-4422(19)30287-x
[12]
Feany, M.B. (2004) New Genetic Insights into Parkinson’s Disease. NewEnglandJournalofMedicine, 351, 1937-1940. https://doi.org/10.1056/nejmp048263
[13]
Horsager, J. and Borghammer, P. (2024) Brain-First vs. Body-First Parkinson’s Disease: An Update on Recent Evidence. Parkinsonism&RelatedDisorders, 122, Article ID: 106101. https://doi.org/10.1016/j.parkreldis.2024.106101
[14]
Borghammer, P., Just, M.K., Horsager, J., Skjærbæk, C., Raunio, A., Kok, E.H., et al. (2022) A Postmortem Study Suggests a Revision of the Dual-Hit Hypothesis of Parkinson’s Disease. NPJParkinson’sDisease, 8, Article No. 166. https://doi.org/10.1038/s41531-022-00436-2
[15]
Witzig, V., Pjontek, R., Tan, S.K.H., Schulz, J.B. and Holtbernd, F. (2024) Modulating the Cholinergic System—Novel Targets for Deep Brain Stimulation in Parkinson’s Disease. JournalofNeurochemistry, 169, e16264. https://doi.org/10.1111/jnc.16264
[16]
Lin, C., Ridder, M.C. and Sah, P. (2023) The PPN and Motor Control: Preclinical Studies to Deep Brain Stimulation for Parkinson’s Disease. FrontiersinNeuralCircuits, 17, Article ID: 1095441. https://doi.org/10.3389/fncir.2023.1095441
[17]
Painous, C., Perissinotti, A. and Martí, M.J. (2019) Is Serotonin Pathology a Good Biomarker inVivo for Early Parkinson’s Disease? AnnalsofTranslationalMedicine, 7, S351-S351. https://doi.org/10.21037/atm.2019.09.80
[18]
Lin, C.-P., Frigerio, I., Bol, J.G.J.M., Bouwman, M.M.A., Wesseling, A.J., Dahl, M.J., et al. (2024) Microstructural Integrity of the Locus Coeruleus and Its Tracts Reflect Noradrenergic Degeneration in Alzheimer’s Disease and Parkinson’s Disease. TranslationalNeurodegeneration, 13, Article No. 9. https://doi.org/10.1186/s40035-024-00400-5
[19]
Iovino, L., Tremblay, M.E. and Civiero, L. (2020) Glutamate-Induced Excitotoxicity in Parkinson’s Disease: The Role of Glial Cells. JournalofPharmacologicalSciences, 144, 151-164. https://doi.org/10.1016/j.jphs.2020.07.011
[20]
Terkelsen, M.H., Hvingelby, V.S. and Pavese, N. (2022) Molecular Imaging of the GABAergic System in Parkinson’s Disease and Atypical Parkinsonisms. CurrentNeurologyandNeuroscienceReports, 22, 867-879. https://doi.org/10.1007/s11910-022-01245-z
[21]
Dirkx, M.F. and Bologna, M. (2022) The Pathophysiology of Parkinson’s Disease Tremor. JournaloftheNeurologicalSciences, 435, Article ID: 120196. https://doi.org/10.1016/j.jns.2022.120196
[22]
Gironell, A., Pascual-Sedano, B., Aracil, I., Marín-Lahoz, J., Pagonabarraga, J. and Kulisevsky, J. (2018) Tremor Types in Parkinson Disease: A Descriptive Study Using a New Classification. Parkinson’sDisease, 2018, Article ID: 4327597. https://doi.org/10.1155/2018/4327597
[23]
Bologna, M., Paparella, G., Fasano, A., Hallett, M. and Berardelli, A. (2019) Evolving Concepts on Bradykinesia. Brain, 143, 727-750. https://doi.org/10.1093/brain/awz344
[24]
Baradaran, N., Tan, S.N., Liu, A., Ashoori, A., Palmer, S.J., Wang, Z.J., et al. (2013) Parkinson’s Disease Rigidity: Relation to Brain Connectivity and Motor Performance. FrontiersinNeurology, 4, Article No. 67. https://doi.org/10.3389/fneur.2013.00067
[25]
Bohnen, N.I., Costa, R.M., Dauer, W.T., Factor, S.A., Giladi, N., Hallett, M., et al. (2021) Discussion of Research Priorities for Gait Disorders in Parkinson’s Disease. MovementDisorders, 37, 253-263. https://doi.org/10.1002/mds.28883
[26]
Tong, S., Wang, R., Li, H., Tong, Z., Geng, D., Zhang, X., et al. (2025) Executive Dysfunction in Parkinson’s Disease: From Neurochemistry to Circuits, Genetics and Neuroimaging. ProgressinNeuro-PsychopharmacologyandBiologicalPsychiatry, 137, Article ID: 111272. https://doi.org/10.1016/j.pnpbp.2025.111272
[27]
Hayley, S., Vahid-Ansari, F., Sun, H. and Albert, P.R. (2023) Mood Disturbances in Parkinson’s Disease: From Prodromal Origins to Application of Animal Models. NeurobiologyofDisease, 181, Article ID: 106115. https://doi.org/10.1016/j.nbd.2023.106115
[28]
Bollu, P.C. and Sahota, P. (2017) Sleep and Parkinson Disease. Missouri Medicine, 114, 381-386. https://pmc.ncbi.nlm.nih.gov/articles/PMC6140184/
[29]
Lofredi, R., Okudzhava, L., Irmen, F., Brücke, C., Huebl, J., Krauss, J.K., et al. (2023) Subthalamic Beta Bursts Correlate with Dopamine-Dependent Motor Symptoms in 106 Parkinson’s Patients. NPJParkinson’sDisease, 9, Article No. 2. https://doi.org/10.1038/s41531-022-00443-3
[30]
Unnisa, A., Dua, K. and Kamal, M.A. (2023) Mechanism of Mesenchymal Stem Cells as a Multitarget Disease—Modifying Therapy for Parkinson’s Disease. CurrentNeuropharmacology, 21, 988-1000. https://doi.org/10.2174/1570159x20666220327212414
[31]
Chen, Y., Kuang, J., Niu, Y., Zhu, H., Chen, X., So, K., et al. (2023) Multiple Factors to Assist Human-Derived Induced Pluripotent Stem Cells to Efficiently Differentiate into Midbrain Dopaminergic Neurons. NeuralRegenerationResearch, 19, 908-914. https://doi.org/10.4103/1673-5374.378203
[32]
Lee, D., Lee, E.C., Lee, J.Y., Lee, M.R., Shim, J. and Oh, J.S. (2024) Neuronal Cell Differentiation of iPSCs for the Clinical Treatment of Neurological Diseases. Biomedicines, 12, Article No. 1350. https://doi.org/10.3390/biomedicines12061350
[33]
Tabar, V., Sarva, H., Lozano, A.M., Fasano, A., Kalia, S.K., Yu, K.K.H., et al. (2025) Phase I Trial of hES Cell-Derived Dopaminergic Neurons for Parkinson’s Disease. Nature, 641, 978-983. https://doi.org/10.1038/s41586-025-08845-y
[34]
Sawamoto, N., Doi, D., Nakanishi, E., Sawamura, M., Kikuchi, T., Yamakado, H., et al. (2025) Phase I/II Trial of iPS-Cell-Derived Dopaminergic Cells for Parkinson’s Disease. Nature, 641, 971-977. https://doi.org/10.1038/s41586-025-08700-0
