Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review
Abstract
1. Introduction
2. Epidemiology, Clinical Features, and Diagnostic Criteria
3. Etiology and Pathogenesis of PD
3.1. Genetic and Environmental Factors and Pathogenesis of PD
3.2. Autosomal-Dominant Genes and PD Pathogenesis
3.3. Autosomal-Recessive Genes and PD Pathogenesis
4. Molecular Mechanisms of PD
4.1. Role of α-Synuclein Aggregation in PD Pathology
4.2. Role of Oxidative Stress (OS) in PD Pathology
4.3. Role of Ferroptosis in PD Pathology
4.4. Role of Mitochondrial Dysfunction in PD Pathology
4.5. Role of Neuroinflammation in PD Pathology
4.6. Role of Gut Dysbiosis in PD Pathology
5. Research Models of PD
6. Therapeutic Strategies for PD
6.1. Commercially Available Drugs for PD
6.1.1. Levodopa
6.1.2. DA Agonists
6.1.3. Catechol-O-Methyltransferase and Monoamine Oxidase Type B Inhibitors
6.1.4. Non-Dopaminergic Targets
6.2. Drugs for PD Treatment Under Clinical Trials
6.3. Phytochemical-Based Therapeutic Strategy for PD Treatment
6.3.1. Phenol
6.3.2. Alkaloids
6.3.3. Flavonoids
6.3.4. Terpenoids
6.3.5. Saponins
7. Discussion and Perspectives
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Mechanism | Role in PD Pathology | Effects |
---|---|---|
α-Synuclein Aggregation | Misfolded α-synuclein forms toxic oligomers and fibrils, accumulating as Lewy bodies in dopaminergic neurons | - Disrupts synaptic function - Impairs protein degradation - Spreads prion-like |
Oxidative Stress (OS) | Excess ROS from mitochondrial impairment, dopamine metabolism, and inflammation | - Lipid peroxidation - DNA/protein damage - α-Synuclein misfolding |
Ferroptosis | Iron-dependent, lipid-peroxide-driven cell death pathway observed in dopaminergic neuron degeneration | - Increased iron accumulation - GPX4 depletion - Membrane lipid peroxidation |
Mitochondrial Dysfunction | Impaired complex I activity in the electron transport chain leads to energy failure and ROS generation | - ATP depletion - Increased oxidative stress - Cytochrome c release and apoptosis |
Neuroinflammation | Activation of microglia and astrocytes promotes chronic inflammation and release of pro-inflammatory cytokines | - TNF-α, IL-1β release - Increased BBB permeability - Further neuron damage |
Gut Dysbiosis | Altered microbiota composition affects gut-brain axis, promoting inflammation and α-synuclein aggregation | - Increased intestinal permeability - Elevated endotoxins (LPS) - Immune activation |
Class | Drug | Therapeutic Applications |
---|---|---|
L-DOPA preparation | L-DOPA/benserazide tablet Carbidopa/L-DOPA tablet Carbidopa/L-DOPA controlled-release tablet | Parkinson’s syndrome Parkinson’s syndrome Parkinson’s syndrome, wearing-off, dyskinesia |
DA agonists | Pramipexole tablet Ropinirole tablet Piribedil Transdermal rotigotine Injected apomorphine | Parkinson’s early syndrome, L-DOPA adjunct, wearing-off, dyskinesia Parkinson’s early syndrome, L-DOPA adjunct, wearing-off, dyskinesia Tremor, DA adjunct Parkinson’s early syndrome, L-DOPA adjunct, wearing-off, dyskinesia Wearing-off, L-DOPA-induced dyskinesias |
N-methyl-D-aspartate receptor antagonist | Amantadine | Parkinson’s early syndrome, L-DOPA adjunct |
Adenosine A2a receptor antagonists | Istradefylline | Wearing-off |
Others | Clozapine | Dyskinesia |
Anticholinergics | Benztropine Trihexyphenidy | Parkinson’s early syndrome, L-DOPA adjunct Parkinson’s early syndrome, L-DOPA adjunct |
COMT inhibitors | Entacapone Opicapone Tolcapone | Wearing-off, dyskinesia Wearing-off, dyskinesia Wearing-off |
MAO-B inhibitors | Selegiline Rasagiline Safinamide Zonisamide | Parkinson’s early syndrome, wearing-off, dyskinesia Parkinson’s early syndrome, L-DOPA adjunct, Wearing-off, Dyskinesia Wearing-off, Dyskinesia Wearing-off |
Therapeutic Strategy | Name | Target and Classification |
---|---|---|
DA receptor agonists | PF-06649751/CVL 751/Tavapadon PF-06669571 PF-06412562 KDT-3594/AM-006 Lu-AF28996 | Small molecular DA D1/D5 agonist Small molecular DA D1 agonist Small molecular DA D1 agonist Small molecular DA agonist Small molecular DA D1/D2 agonist |
Anti-α-synuclein aggregation therapy | Prasinezumab/PRX002/RO7046015 MEDI-1341/TAK-341 Lu AF82422 UCB7853 UCB 0599 Kenterin/Enterin-01 Ambroxol | Monoclonal antibody Monoclonal antibody Monoclonal antibody Monoclonal antibody Small molecular SNCA antagonists Small molecular SNCA antagonist Small molecular decrease in the cerebrospinal fluid α-synuclein level |
Targeting ferroptosis | Cu(II)ATSM | Small molecular Peroxynitrite scavenger |
Serotonin receptor agonists or antagonists | Landipirdine/SYN120/RO-5025181 SEP-363856 | Small molecular dual 5-HT6/5-HT2 antagonist Small molecular 5-HT1A agonist |
Others | CNM-Au8 NLY01/NLY01-AD | Small molecular Small molecular GLP1R agonist |
Gene therapy | AAV2-GDNF LY3884961/PR001A | AAV2-GDNF delivered to the putamen Glucocerebrosidase gene therapy by intra cisterna magna administration |
Cell-based therapy | NTCELL ISC-hpNSC ANGE-S003 | Immunoprotected (alginate-encapsulated) porcine choroid pplexus cells Neural stem cells Neural stem cell |
Botanical-based medication | DA 9805 Hypoestoxide WIN-1001X | Natural compounds Plant-based herbal dry powder Plant-based herbal extract |
Kinase inhibitors | SUN-K706/Vodobatinib/SCC138/K0706 Nilotinib/Tasigna/AMN-107 Radotinib Dihydrochloride/IY-5511 BIIB-122/DNL151 DNL-201 | Small molecular Bcr-Abl antagonist Small molecular Bcr-Abl antagonist Small molecular Bcr-Abl antagonist Small molecular LRRK2 antagonist Small molecular LRRK2 antagonist |
Muscarinic and nicotinic acetylcholine receptor agonists | Blarcamesine/AF710B/ANAVEX 2-73 | Small molecular Muscarinic acetylcholine receptor M1 agonist |
Acetylcholinesterase antagonists | Buntanetap/ANVS-401 | Small molecular AchE antagonist/TAU antagonist |
Adenosine A2a receptor antagonists | KW-6356 Caffeine | Small molecular adenosine A2A receptor antagonist Small molecular selective adenosine A2A antagonist |
N-methyl-D-aspartate receptor (NMDAR) modulators | NBTX 001 NYX-458 DAAOI-P | Small molecular NMDAR modulato Small molecular NMDAR modulator Small molecular D-amino acid oxidase inhibitor |
Class | Name | Targets |
---|---|---|
Phenol | Curcumin Resveratro | Trk/PI3K, JNK PI3K/Akt, SIRT 1, MAPK |
Saponin | Ginsenoside Rb1 Ginsenoside Rg3 | NF-κB NF-κB |
Terpenoid | Celastrol | MAPK, Nrf2-NLRP3-caspase-1 |
Flavonoid | Puerarin Baicalein | Fyn/GSK-3β, PI3K/Akt NLRP3/caspase-1/gasdermin D, BDNF/TrkB/CREB |
Alkaloid | Berberine Isorhynchophylline | AMPK ASK1/JNK |
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Khan, M.S.; Nasiripour, S.; Bopassa, J.C. Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review. Int. J. Mol. Sci. 2025, 26, 6416. https://doi.org/10.3390/ijms26136416
Khan MS, Nasiripour S, Bopassa JC. Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review. International Journal of Molecular Sciences. 2025; 26(13):6416. https://doi.org/10.3390/ijms26136416
Chicago/Turabian StyleKhan, Muhammad S., Somayyeh Nasiripour, and Jean C. Bopassa. 2025. "Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review" International Journal of Molecular Sciences 26, no. 13: 6416. https://doi.org/10.3390/ijms26136416
APA StyleKhan, M. S., Nasiripour, S., & Bopassa, J. C. (2025). Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review. International Journal of Molecular Sciences, 26(13), 6416. https://doi.org/10.3390/ijms26136416