Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine-producing neurons.
Dopamine plays an important role in PD development.
Here are some key facts:
- Dopamine is a chemical messenger in the brain involved in movement, motivation, and mood.
- Loss of dopamine-producing neurons causes the motor symptoms of PD like tremors, rigidity, and slow movements.
- Dopamine can become unstable and produce toxic byproducts that damage neurons.
- Dopamine interacts with PD-related genes like α-synuclein and LRRK2 to promote neurodegeneration.
- Strategies that control dopamine levels and metabolism may help protect neurons from damage.
Source: Transl Neurodegener. 2023
What is Dopamine?
Dopamine is a neurotransmitter – a chemical messenger that allows communication between neurons in the brain.
It is synthesized in neurons located in an area deep in the brain called the substantia nigra.
Dopamine released by these neurons regulates important functions like controlling movement, motivated behavior, mood, learning, and memory.
Dopamine’s Role in Parkinson’s Disease
In PD, the dopamine-producing neurons in the substantia nigra progressively die off.
This causes dopamine levels to drop in brain regions these neurons project to, like the striatum.
Loss of dopamine in the striatum leads to the motor symptoms of PD including tremors, rigidity, slow movements, and balance problems.
Current PD medications aim to boost dopamine levels.
Levodopa, the most commonly prescribed PD drug, is converted to dopamine in the brain.
However, these medications lose effectiveness over time and do nothing to slow the ongoing death of dopamine neurons.
Dopamine Instability and Toxic Metabolites
Dopamine is chemically unstable and easily oxidized, especially at the alkaline pH found inside neurons.
Oxidation causes dopamine to lose electrons and become reactive.
This reactive dopamine can then bind to and damage proteins and other cellular components.
Enzymes that break down dopamine called monoamine oxidases (MAOs) also generate toxic dopamine byproducts like DOPAL.
In addition, free iron and copper ions present in the substantia nigra readily interact with dopamine to accelerate its oxidation.
The reactive dopamine oxidation products are:
- Reactive oxygen species (ROS) – oxygen free radicals that cause oxidative stress.
- Dopamine quinones (DAQs) – molecules that bind and disable proteins.
- DOPAL – aldehyde that reacts with proteins.
Together, these damaging dopamine metabolites place great oxidative stress on dopamine-producing neurons, making them more vulnerable to degeneration.
Dopamine & Genes in Parkinsons Disease
Several genes linked to rare inherited forms of PD impact dopamine metabolism and stability. These include:
- α-Synuclein – α-Synuclein protein clumps form the Lewy bodies seen in PD brains. Dopamine oxidation makes α-synuclein aggregate more rapidly. Toxic dopamine metabolites also bind α-synuclein, which impairs its normal function in vesicles and promotes α-synuclein aggregation.
- LRRK2 – The most common PD genetic mutation is in the LRRK2 gene. Mutant LRRK2 protein increases dopamine synthesis, which leads to more oxidative stress on dopamine neurons when dopamine oxidizes.
- Parkin – Parkin protein tags damaged proteins for destruction. Dopamine oxidation inactivates Parkin by binding to it. Faulty Parkin then cannot clear unwanted aggregated proteins.
- DJ-1 – Normal DJ-1 protein protects neurons from oxidative stress. Dopamine oxidation disables DJ-1, preventing its antioxidative effects.
- GBA1 – Mutations in the GBA1 gene that codes for the GCase enzyme are a major PD genetic risk factor. Dopamine oxidation inhibits GCase and impairs lysosome function, promoting α-synuclein buildup.
- These interactions show that increased dopamine oxidation can enhance the toxicity of PD genetic mutations.
Oxidized dopamine byproducts disable protective mechanisms that keep neurons healthy.
Protecting Neurons from Dopamine Damage
Since unstable dopamine is neurotoxic, strategies that stabilize dopamine and block its toxic effects show promise for protecting dopamine neurons in PD.
- Reducing dopamine synthesis – Inhibiting the enzyme tyrosine hydroxylase slows dopamine production, which lowers oxidation. The drug alpha-methyltyrosine prevents neurodegeneration in PD models by reducing dopamine synthesis.
- Increasing dopamine breakdown – MAO inhibitors prevent the buildup of oxidized dopamine. DOPAL-detoxifying enzymes like ALDH1A1 also show neuroprotective effects in PD models.
- Antioxidants – Glutathione, vitamin C, and cysteine react with toxic dopamine quinones and DOPAL to neutralize them. Plant polyphenols like those in green tea may also deactivate these neurotoxins.
- Chelators – Iron and copper ions accelerate dopamine oxidation, so metal-binding agents prevent their neurotoxic effects.
- Dopamine storage – More vesicle storage protects dopamine from oxidizing in the cytosol. Overexpressing the vesicular transporter VMAT2 reduces dopamine oxidation damage.
- Targeting dopamine-PD gene interactions – Blocking pathogenic α-synuclein aggregation and restoring normal Parkin, DJ-1, and GCase protein activities would mitigate dopamine oxidation damage in genetic forms of PD.
The interactions between dopamine and PD genes indicate combined treatment strategies may work best.
For example, an MAO inhibitor plus iron chelator combination protects on two fronts by reducing dopamine oxidation and oxidized dopamine reactivity.
The Future of Dopamine-Targeted Therapies
While current dopamine-boosting drugs can temporarily improve PD motor symptoms, new therapies aimed at stabilizing dopamine metabolism and blocking its toxic effects offer hope for neuroprotection.
Further research on the complex interplay between dopamine and PD genes will uncover additional therapeutic targets.
Dopamine-focused treatments that address the root cause of PD neurodegeneration could significantly slow disease progression.
Managing unstable dopamine may be the key to preserving dopamine neurons and protecting brain function in PD.
References
- Study: Role of dopamine in pathophysiology of Parkinson’s disease
- Authors: Zhi Dong Zhou et al. (2023)
