Jonathon Cattoor

Background: Parkinson’s Disease (PD) is a debilitating neurologic disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain leading to symptoms such as bradykinesia, rigidity, and resting tremor. There are an estimated 12.5 million individuals worldwide currently living with PD, and that number is estimated to leap to 25.1 million by 2050.¹ The exact cause of PD is unknown, but multiple factors have been thought to play a role in its development. These include environmental exposures, complex changes with aging, and mutations in genes such as LRRK2.^2-3 Traditional therapies such as levodopa/carbidopa, dopamine agonists, and MAOI’s are targeted towards replacing the dopamine that has been lost as a result of dopaminergic neuronal cell death.^3-4 In recent years, Vesicular Monoamine Transporter 2 (VMAT2)  –– the transporter involved in dopamine vesicular packaging –– has shown promise as a potential target for PD therapy.⁵ Studies have demonstrated that targeting this transporter during the earliest stages of PD may reduce dopaminergic neuron degeneration and subsequently reduce the clinical symptomology and progression of PD.^5-9

Objective: An upstream mechanism in the pathogenesis of PD was studied as a novel target for pharmacotherapy with the aim of reducing disease progression.

Search Methods: PubMed and Google Scholar searches were made using key words such as “VMAT2”, “Parkinson’s Disease”, “Neuromelanin”, and “Alpha-synuclein”. Only articles published between 2018-2025 were used.

Results: The included studies indicate that VMAT2 dysfunction facilitates the spontaneous oxidation of cytosolic dopamine to neuromelanin precursors in presynaptic neurons of the substantia nigra.⁵ Neurons that were introduced to high levels of neuromelanin demonstrated an increased accumulation of alpha-synuclein, a protein implicated in the destruction of these neurons.⁶ This was accomplished through introducing the LRRK2 knock-in mutation which diminishes the function of VMAT2 and enhances the dopamine transporter (DAT), thereby elevating cytosolic dopamine levels and encouraging neuromelanin synthesis.⁸ The cells with low VMAT2 function demonstrated higher levels of both neuromelanin and alpha-synuclein, contributing to their death^7-8. Additionally, mice with artificially reduced VMAT2 function scored lower on olfactory function tests, suggesting that the clinical symptomology of PD may be reliant upon VMAT2 function⁹. Current pharmaceuticals, such as tricyclic and tetracyclic antidepressants, have been shown to upregulate the VMAT2 transporter in cell lines when exposed to these drugs for an extended period.⁵

Conclusions: These studies have demonstrated a pathologic sequela of events that may occur in the earliest stages of PD. Instead of treating PD by replacing the dopamine that has been lost because of neuronal degeneration, therapies that target these neurons during their earliest stages of demise may provide promise into slowing the progression of PD. Upregulating VMAT2 before significant neuronal cell death has occurred may salvage the substantia nigra by halting neuromelanin accumulation, alpha-synuclein pathology, and subsequent cell death. The end goal of this target would be to slow PD progression and improve the quality of life with those suffering from the disease.

Work Cited:

1. com. Published 2021. https://www.bmj.com/content/388/bmj-2024-080952‌
2. Bucher ML, Barrett CW, Moon CJ, et al. Acquired Dysregulation of Dopamine Homeostasis Reproduces Features of Parkinson’s Disease. npj Parkinson’s Disease.2020;6(1). doi:10.1038/s41531-020-00134-x
3. Raza C, Anjum R, Shakeel N ul. Parkinson’s disease: Mechanisms, Translational Modelsand Management Strategies. Life Sciences. 2019;226:77-90. doi:10.1016/j.lfs.2019.03.057
4. Kobylecki C. Update on the Diagnosis and Management of Parkinson’s Disease. ClinicalMedicine. 2020;20(4):393-398. doi:10.7861/clinmed.2020-0220
5. Wang X, Ilias Marmouzi, Peter, et al. Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants. Neuropsychopharmacology. Published online July 26, 2024. doi:https://doi.org/10.1038/s41386-024-01914-2
6. Gonzalez-Sepulveda M, Compte J, Cuadros T, et al. In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease. Brain. 2023;146(3):1040-1052.doi: https://doi.org/10.1093/brain/awac445
7. Chocarro J, Rico AJ, Ariznabarreta G, et al. Neuromelanin Accumulation Drives Endogenous Synucleinopathy in Non-Human Primates. Brain. 2023;146(12):5000-5014.doi:10.1093/brain/awad331
8. Domenicale C, Mercatelli D, Albanese F, et al. Dopamine Transporter, PhosphoSerine129 α-Synuclein and α-Synuclein Levels in Aged LRRK2 G2019S Knock-In and Knock-Out Mice. Biomedicines. 2022;10(4):881. doi: https://doi.org/10.3390/biomedicines10040881
9. Ma K, Han C, Zhang G, et al. Reduced VMAT2 expression exacerbates the hyposmia in the MPTP model of Parkinson’s disease. Biochem Biophys Res Commun. 2019;513(2):306-312. doi:10.1016/j.bbrc.2019.03.159