Parkinson’s disease arises from a combination of processes that ultimately result in the loss of neurons, particularly those responsible for producing dopamine.
The development of Parkinson's disease is driven by several key mechanisms, including:
- Impaired autophagy and the accumulation of proteins
- Mitochondrial dysfunction
- Oxidative stress and damage
- Dysregulation of the gut microbiome
- Inflammation
- Additional contributing factors
Together, these mechanisms result in the dysfunction and degeneration of neurons in the brain, particularly those responsible for producing dopamine.
Dopamine is a small messenger molecule that specific neurons release between them to communicate with each other.
Dopamine is particularly produced by neurons involved in movement and planning movement. Billions of neurons in our brain (and neurons running from our spinal cord to our muscles) use dopamine to communicate with each other and to control and execute movement.
In Parkinson’s disease, dopamine-producing neurons in the substantia nigra (“black substance”) die off.
The substantia nigra is a region found deep inside the brain, consisting of neurons that produce dopamine (hence they are called “dopaminergic neurons''). The substantia nigra plays a very important role in movement and balance.
Normally, there are around 550,000 dopamine-producing neurons in the substantia nigra. When around 70% of these neurons have died off, people experience the first symptoms of Parkinson’s disease, such as tremor, rigidity in movements, stiffness, or difficulty walking.
However, in Parkinson’s disease, other brain regions get affected as well. In the early stages of the disease, it’s possible that more “caudal” (meaning lower) brain regions are becoming more and more damaged, like the brainstem, and perhaps even the intestinal nerves in the gut.
In the later stages of the disease, we see that more “higher” brain regions (located above the substantia nigra) get damaged, such as the neocortex. This explains why in later-stage Parkinson’s disease also problems with memory and cognition appear.
So what causes Parkinson’s disease? Scientists are still figuring this out, but there are already strong clues that the following mechanisms play major roles in the disease:
1. Impaired autophagy and protein accumulation
Autophagy is the very important process by which our cells break down “waste” materials, including proteins.
Each of our cells contain millions of proteins. Proteins carry out most of the functions in our cells, and serve also as building blocks for our cells.
In Parkinson’s disease (and also during normal aging) there is the accumulation of specific proteins.
One protein that notably accumulates in Parkinson’s disease is alpha-synuclein. This is a small protein (containing 140 amino acids) which is normally involved in transportation of small vesicles in our cells, but can also be involved in other functions, such as DNA repair (R).
This heaping up of proteins in brain cells impedes their proper function, which can ultimately lead to their dysfunction and death.
Normally, autophagy is a series of processes in which proteins are broken down. In Parkinson’s patients, autophagy functions less well, leading to the accumulation of proteins and other waste materials, including even whole cell organelles (components), like the mitochondria (see below).
Learn more about the role of autophagy and protein accumulation in Parkinson's disease here.
2. Mitochondrial dysfunction
The mitochondria are the power plants of the cell. Cells contain hundreds to thousands of mitochondria.
The food we eat and the oxygen we breathe mainly serve as fuel for the mitochondria to produce the energy that our cells need to carry out their function.
In Parkinson’s disease, mitochondrial function declines. This causes brain cells to have less energy, causing them to function less well and perish eventually.
There are also some genetic forms of Parkinson’s disease (caused by mutations in genes) which lead to mitochondrial dysfunction.
For example, a mutation in a gene called PRKN causes malfunction of a protein called Parkin. This protein normally tags damaged or malfunctioning mitochondria for breakdown.
However, this mutation impedes Parkin from doing its job, so old or damaged mitochondria are not tagged for breakdown, which leads to the accumulation of damaged mitochondria in neurons, which contributes to neuronal cell death.
Scientists can also induce Parkinson-like symptoms in mice by giving them substances that are toxic for mitochondria, such as rotenone, MPTP, or paraquat.
Some people who took drugs that contained MPTP suffered from extensive mitochondrial damage, causing irreversible Parkinson’s symptoms, like tremor, rigidity, difficulty moving and other symptoms.
Learn more about the role of mitochondria in Parkinson's disease here.
3. Oxidative stress and damage
Oxidative stress is increased in people with Parkinson’s disease.
This is caused by increased levels of “free radicals”.
Free radicals are highly reactive small particles (like oxygen radicals) that steal electrons from other substances in our cells, thereby damaging them.
This “stealing of electrons” is called “oxidation”. Normally, electrons function as a “glue” by which atoms are glued (joined) together, so stealing them can damage atoms and molecules.
In Parkinson’s disease, neurons that produce dopamine suffer from a lot of oxidative damage.
One reason for this is that dopamine is a molecule that gets easily oxidized.
This could help to explain why mainly dopaminergic neurons get so quickly damaged by free radicals.
Also, mitochondria are very susceptible to oxidative damage. Mitochondrial damage also plays an important role in Parkinson’s, as explained earlier.
Interestingly, scientists can induce Parkinson-like symptoms in lab animals by giving them toxins that oxidize neurons in the brain.
Also, some pesticides can cause oxidative damage in brain regions involved in Parkinson’s disease (R). Studies show an association between people living in agricultural areas where higher levels of pesticides are used and the risk of Parkinson’s disease (R).
Learn more about the role of oxidative stress in Parkinson's disease here.
4. A dysregulated gut microbiome (gut dysbiosis)
The gut plays a significant role in Parkinson’s disease. Some scientists even believe that Parkinson’s starts in the gut (R,R).
Our gut contains trillions of bacteria (and viruses and yeast) which secrete many substances that leak from the gut into the bloodstream and impact the brain.
The gut also contains many immune cells (around 70% of the immune system is found in the gut), which also impacts brain health and brain inflammation.
The gut also contains many nerves, which relay signals from the gut to the brain, and can also help to spread toxic proteins from the gut to the brain.
Some ways an unhealthy gut can impact Parkinson’s disease:
- Specific unhealthy bacteria, found more in Parkinson’s patients, secrete substances that are damaging to the brain.
- A leaky gut, also called “increased gastro-intestinal permeability”, causes damaging substances to leak from the gut into the bloodstream, reaching the brain and causing inflammation and other problems in the brain.
- Some bacteria secrete substances, like the curli protein, which can induce the aggregation of other proteins, such as alpha-synuclein (alpha-synuclein is the main protein that accumulates in the brains of Parkinson’s disease patients) (R).
- Aggregation of proteins can spread like a domino-effect from the gut to the brain, via the vagus nerve, which connects the gut and the brain.
- Studies have shown that alpha-synuclein, a protein that aggregates to form toxic clumps in the brains of Parkinson’s disease patients, can also be found in the nervous system of the gut.
- Gastrointestinal symptoms, such as constipation, often precede the motor symptoms of Parkinson’s disease by several years.
These and other mechanisms and observations hint at an important role of the gut microbiome in the origin and progression of Parkinson’s disease.
Learn more about the role of the gut in Parkinson’s disease here.
5. Inflammation
Inflammation is probably more a contributing factor to Parkinson’s disease than a primary cause.
In other words, iInflammation can increase the risk of Parkinson’s disease, or accelerate the progress of the disease.
Interestingly, some studies show that people who take anti-inflammatory drugs for a long time (for other indications, like osteoarthritis) have reduced risk of Parkinson’s disease.
However, one has to be careful with long-term intake of such drugs, given they can have significant side effects, like gastrointestinal bleeding or kidney dysfunction.
When we age, inflammation increases in the body (called “inflammaging”) and this also damages neurons in the brain, including in the substantia nigra, the part of the brain where Parkinson’s disease originates.
6. Genetics and Parkinson’s disease
Most cases of Parkinson’s disease are not genetic. However, around 10% of cases are caused by specific genetic mutations. This means people have a mutation in their DNA that causes Parkinson’s disease.
Often, people with such mutations get Parkinson’s disease at a much earlier age, for example being in their forties or fifties. This disease often also runs in their family.
Many mutations in genes have been identified that can cause genetic, early-onset Parkinson’s disease.
For example, mutations in the gene coding for parkin leads to less breakdown of old or damaged mitochondria, which leads to the accumulation of malfunctioning, damaged mitochondria.
However, most Parkinson’s disease (around 90%) is not genetic.
This is called “sporadic” Parkinson’s disease, and it often happens when people are older, being in their sixties or seventies. There is no familial predisposition for Parkinson’s disease.
Learn more about the genetic causes of Parkinson’s disease here.
7. Other causes of Parkinson’s disease
Besides the mechanisms highlighted above, there could be various other mechanisms involved in Parkinson’s disease, such as:
- Epigenetic dysregulation: the epigenome regulates gene expression. In Parkinson’s disease, a dysregulated epigenome could cause protective genes to be not expressed anymore, and damaging genes to be activated.
- Retrotransposon activation: retrotransposons are a form of “parasitic DNA” which makes copies of itself, inserting itself randomly in the DNA, which causes genomic instability and inflammation in neurons.
- Transcriptional dysregulation: the transcriptome also determines how proteins are made. It consists of RNA strands (encoding the instructions to build proteins), RNA-binding proteins such as TDP-43 and FUS, and modifications of RNA molecules (such as N6-methyladenosine/m6A). When these processes are not running properly, this could lead to neurodegenerative diseases.
- Impaired lipid metabolism: the brain needs various fats to stay healthy; altered lipid metabolism, including dysfunction in ceramide, sphingolipid, or cholesterol pathways, can affect neuronal membrane integrity, alpha-synuclein aggregation, and neuroinflammation.
- Viral and bacterial infections of the brain: certain infections, such as those caused by herpes simplex virus, influenza, or Helicobacter pylori, have been implicated in Parkinson’s disease through inflammatory and neurotoxic mechanisms.
- Brain trauma: head injuries and chronic traumatic encephalopathy (CTE) have been linked to an increased risk of Parkinsonian symptoms due to cumulative neuronal damage.
- Reduced blood flow in the brain: abnormalities in cerebral blood flow or vascular integrity may contribute to hypoxic damage and neuronal loss.
- Environmental toxins: exposure to chemicals, pesticides (e.g., paraquat, rotenone), herbicides and other toxins can lead to dopaminergic neuronal death through mitochondrial and oxidative pathways.
- Toxic metals: accumulation of metals such as iron, copper, and manganese in the brain can contribute to neurodegeneration through oxidative stress and protein aggregation.
- Specific drugs: drugs like methamphetamine (used to treat ADHD), some statins, anti-nausea medications (dopamine antagonists like metoclopramide), and antipsychotics (dopamine receptor blockers) can increase the risk of Parkinson symptoms, or Parkinson’s disease itself.
Generally, it could be likely that these processes are less relevant, and mainly increase the risk of Parkinson’s disease, but not really causing the disease in most cases.
In other words, these processes create more stress on neurons that are already stressed by more fundamental causes of Parkinson’s disease as listed above (e.g. impaired autophagy, oxidative damage, and mitochondrial dysfunction).
For example, pesticides or too high levels of iron can cause mitochondrial and oxidative damage, leading to an increased risk of Parkinson's disease.
Learn more about the latest treatments for Parkinson's disease here.
