Oxidative stress plays a major role in Parkinson’s disease.
But first: what is oxidative stress?
Oxidative stress refers to an overabundance of free radicals, which damage cell components.
Free radicals are tiny particles that steal electrons from other atoms (stealing electrons is called “oxidation”). Since electrons serve as the "glue" holding atoms together in molecular structures, this electron theft disrupts and damages those structures.
In other words, free radicals damage proteins, DNA, membrane lipids and other cell components.
Free radicals are also called “reactive oxygen species (ROS)” given they quickly “react” (steal electrons) from surrounding molecules.
Examples of free radicals are superoxide, hydroxyl radicals, and hydrogen peroxide.
Most free radicals are byproducts of normal cellular metabolism. Particularly, our mitochondria produce lots of free radicals as a byproduct of producing energy for our cells.
When too many free radicals are produced, cells and their components become damaged, which eventually can lead to their death.
Mechanisms of Oxidative Stress in Parkinson's Disease
Several mechanisms contribute to oxidative stress in Parkinson’s disease, creating a vicious cycle of cellular damage, specifically in the cells that produce dopamine:
1. Mitochondrial Dysfunction
Mitochondria are the primary source of free radicals in neurons. In Parkinson’s disease, mitochondria become damaged (learn more about the role of damaged mitochondria in Parkinson’s disease here), particularly in cells in the substantia nigra, a brain region involved in movement.
This mitochondrial damage causes the generation of high amounts of free radicals within neurons, damaging them.
Some genetic causes of Parkinson’s disease involve mutations in genes such as PINK1 and PRKN, which disrupt mitochondrial quality control, leading to damaged mitochondria that produce large amounts of free radicals, causing oxidative stress.
2. Dopamine Metabolism
Neurons that produce dopamine (and which die off in Parkinson’s disease) are inherently vulnerable to oxidative stress due to various reasons:
- Dopaminergic neurons are metabolically very active, given they have to fire a lot, and also have an extensive dendritic network (having lots of branches making connections with other neurons). This high metabolic demand of dopaminergic neurons requires their mitochondria to work hard, producing more free radicals and also damaging the mitochondria over time.
- Dopamine is readily oxidized (forming dopamine quinones). Oxidized dopamine tends to react with cell components, damaging them.
- Enzymatic pathways that break down dopamine (via the enzyme monoamine oxidase) also produce free radicals.
3. Neuroinflammation
Chronic inflammation in the brain of Parkinson’s disease involves (over)activated immune cells and supporting cells, like microglia and astrocytes.
These cells release pro-inflammatory cytokines and free radicals. This inflammatory milieu perpetuates oxidative stress, creating a feed-forward loop of neuronal damage and immune activation.
4. Alpha-Synuclein Aggregation
In Parkinson’s disease, a specific protein, called alpha-synuclein, tends to accumulate in the brain regions involved in Parkinson’s disease.
The accumulation of alpha-synuclein in neurons disrupts mitochondrial function of these cells, and also promotes free radical production.
This oxidative stress, in turn, accelerates alpha-synuclein aggregation (by damaging the alpha-synuclein so it becomes more prone to clump together), highlighting a bidirectional relationship between these processes.
5. Environmental Factors
Environmental toxins such as pesticides (e.g., paraquat and rotenone), heavy metals, and specific foods (like a high-sugar diet) are known to induce oxidative stress in brain cells.
6. Genetic Factors
In cases of genetic Parkinson’s disease, some genetic mutations, such as those in LRRK2 and DJ-1, reduce cellular antioxidant defenses of neurons, rendering these cells more susceptible to oxidative damage.
Consequences of Oxidative Stress in Parkinson's Disease
Oxidative stress contributes to Parkinson’s disease through multiple mechanisms, such as:
- Lipid peroxidation: free radicals attack polyunsaturated fatty acids in neuronal membranes, leading to lipid oxidation. This compromises membrane integrity and disrupts cellular signaling.
- Protein oxidation: free radicals modify proteins, impairing their function and promoting aggregation. For example, oxidized alpha-synuclein is more prone to form toxic aggregates.
- DNA damage: free radicals induce DNA damage, which triggers genomic instability and impairs neuronal survival.
- Mitochondrial damage: free radicals exacerbate mitochondrial dysfunction, further amplifying free radical production in a self-perpetuating cycle.
Conclusion
Oxidative stress plays an important role in Parkinson’s disease, involving mitochondrial dysfunction, dopamine metabolism, neuroinflammation, and protein aggregation, among many other things.
Understanding the molecular underpinnings of oxidative stress in Parkinson’s disease provides valuable insights into its origin, and highlights potential therapeutic avenues.
While significant challenges remain, targeting oxidative stress holds promise for slowing disease progression and improving the quality of life for individuals with Parkinson’s disease.
It’s possible to substantially reduce free radical stress by the foods we eat, which contain substances that better protect (brain) cells against oxidative damage, such as blue fruit, vegetables, specific vitamins and minerals.
