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Parkinson's disease (PD) is a prevalent neurodegenerative disorder with complex origins involving environmental and genetic factors. Key mechanisms include α-synuclein aggregation, oxidative stress, mitochondrial dysfunction, and gut dysbiosis, making treatment challenging. Diagnosis is hindered by long latency together with complexity, and current therapies offer limited efficacy and side effects. The incidence of Parkinson's disease (PD) increases with age, particularly affecting those over 60 years old, with rates exceeding 3% in those over 80.[1] Men are more likely to develop PD than women, possibly due to lifestyle and environmental factors. Environmental toxins and dietary habits, such as smoking and caffeine consumption, may influence disease risk.

PD presents with both motor and non-motor symptoms.[2] Motor symptoms include bradykinesia, muscle stiffness, tremors, and gait difficulties. Tremor-dominant and non-tremor-dominant PD are distinguished based on symptoms, with the former progressing more slowly. Non-motor symptoms like olfactory dysfunction, cognitive decline, and sleep problems often precede motor symptoms. PD progression leads to complications like dyskinesia, psychosis, and fluctuations in symptoms. Neurodegeneration in specific brain regions, such as the substantia nigra, and the accumulation of α-synuclein protein contribute to PD pathology. Diagnosis relies on clinical symptoms, imaging tests like MRI and DAT-SPECT, and occasionally genetic testing.[3] Despite advancements, genetic testing remains limited but may become more common as genetic links to PD become clearer.

PD is known to be a complex neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra region of the brain. Several molecular and cellular changes contribute to the pathogenesis of PD.

  1. α-synuclein aggregation: α-synuclein is a protein that plays a role in synaptic vesicle dynamics and intracellular trafficking.[4] In PD, α-synuclein aggregates abnormally, forming insoluble fibrils and toxic oligomers. These aggregates are believed to contribute to neuronal dysfunction and death.

  2. Oxidative stress: Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses. In PD, increased oxidative stress leads to damage to cellular components such as proteins, lipids, and DNA, contributing to neuronal degeneration.[5]

  3. Ferroptosis: Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. In PD, dysregulation of iron metabolism and lipid peroxidation lead to ferroptotic cell death, particularly in dopamine-producing neurons.[6]

  4. Mitochondrial dysfunction: Mitochondria are the energy-producing organelles in cells, and dysfunction in these organelles is implicated in PD pathogenesis.[7] Mutations in mitochondrial genes, environmental toxins, and impaired mitochondrial quality control mechanisms contribute to mitochondrial dysfunction, leading to energy depletion and increased oxidative stress.

  5. Neuroinflammation: Neuroinflammation involves the activation of immune responses in the brain, including microglial activation and cytokine production. Chronic neuroinflammation exacerbates neuronal damage in PD and may contribute to disease progression.[8]

Understanding these molecular and cellular mechanisms is crucial for the development of effective treatments for PD. Targeting these pathways may help alleviate symptoms and slow disease progression in affected individuals.

Currently, Levodopa (L-DOPA) remains a primary treatment for PD clinically but is associated with motor complications like dyskinesias due to pulsatile dopamine receptor stimulation. Novel sustained-release formulations and continuous delivery methods are being developed to address these issues. Dopamine agonists, targeting D2 receptors, offer longer half-lives than L-DOPA but may cause sleepiness and impulse control problems. Another widely used drug, Apomorphine, acting on both D1 and D2 receptors, shows promise in reducing dyskinesias when administered continuously. Catechol-O-methyltransferase (COMT) inhibitors like entacapone improve L-DOPA bioavailability by inhibiting its peripheral metabolism. Monoamine oxidase type B (MAO-B) inhibitors like selegiline prolong dopamine's effects by inhibiting its breakdown, with safinamide emerging as a reversible alternative. Several non-dopaminergic targets are also explored to address L-DOPA complications and non-motor symptoms like depression and cognitive dysfunction. Amantadine is used for dyskinesia, while cholinesterase inhibitors help with cognitive issues. Clozapine is effective for psychotic symptoms, and various pharmacological options exist for managing autonomic dysfunction. These treatments aim to alleviate symptoms and improve quality of life for PD patients.[9] Although there is currently no cure for Parkinson's disease in clinical practice, multiple drugs are being developed or undergoing clinical trials, perhaps offering hope for a cure in the future.

References

1. Pringsheim, T., et al., The prevalence of Parkinson's disease: a systematic review and meta-analysis. Mov Disord, 2014. 29(13): p. 1583-90.

2. Ascherio, A. and M.A. Schwarzschild, The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol, 2016. 15(12): p. 1257-1272.

3. Postuma, R.B., et al., Validation of the MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord, 2018. 33(10): p. 1601-1608.

4. Melki, R., Role of Different Alpha-Synuclein Strains in Synucleinopathies, Similarities with other Neurodegenerative Diseases. J Parkinsons Dis, 2015. 5(2): p. 217-27.

5. Trist, B.G., D.J. Hare, and K.L. Double, Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease. Aging Cell, 2019. 18(6): p. e13031.

6. Do Van, B., et al., Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC. Neurobiol Dis, 2016. 94: p. 169-78.

7. Subramaniam, S.R. and M.F. Chesselet, Mitochondrial dysfunction and oxidative stress in Parkinson's disease. Prog Neurobiol, 2013. 106-107: p. 17-32.

8. Sommer, A., et al., Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model. J Neuroinflammation, 2016. 13(1): p. 174.

9. Dong-Chen, X., et al., Signaling pathways in Parkinson's disease: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther, 2023. 8(1): p. 73.