The symptoms of Parkinson’s disease are caused by the dying of neurons in brain regions which are involved in dopamine production.
Dopamine is a small messenger molecule that neurons spray between themselves to communicate with each other.
Dopamine is particularly important for neurons that are involved in movement. Billions of neurons in our brain (and 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, we see the dying of neurons in the substantia nigra (“black substance”), which is a region found deep inside the brain. These neurons 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 of these dopamine-producing neurons in the substantia nigra in the brain. When around 70% of these neurons have died off, people experience the first overt symptoms of Parkinson’s disease: tremor, rigidity in movements, stiffness, difficulty walking and other problems.
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 getting damaged, like in the brainstem, and perhaps even in the intestinal nerves in the but.
In the later stages of the disease, we see that more “higher” brain regions (so located above the substantia nigra) get damaged, like the neocortex. This also 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 are involved in the disease:
1. 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, we see that mitochondria function declines.
There are also 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 their accumulation in neurons, which can contribute 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, and paraquat.
It was also discovered that 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.
2. Protein accumulation
Each of our cells contain millions of proteins. Our DNA contains the instructions to build around 20,000 different 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 noteable 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).
In people with Parkinson’s disease, there is accumulation (aggregation) of alpha-synuclein protein.
This heaping up of proteins in brain cells impedes their proper function, which can ultimately lead to their dysfunction and death.
3. A disturbed gut microbiome (gut dysbiosis)
Some scientists believe that Parkinson’s starts in the gut, or that the gut at least plays an important role in the origin of Parkinson’s disease (R,R).
For example, according to one hypothesis, alpha-synuclein (a protein found in neurons) starts to accumulate in neurons in the gut. These protein aggregates start to move upwards via nerves that connect the gut to the brain, for example via the vagus nerve.
Arguments for this are the following:
- There are bacteria in the gut that can produce proteins, like the curli protein, that 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).
- Alpha-synuclein can have a “prion” like effect, namely an alpha-synuclein protein can induce other alpha-synuclein proteins to aggregate (clump together), causing a chain reaction that can spread through the nerves and brain regions. This way, alpha-synuclein can start in the gut and spread from the gut to the brain via the nerves that connect the gut with the brain (R,R).
- Aggregates of alpha-synuclein (a protein that clumps together in Parkinson’s disease) have been found in the gut and in the nerves connecting the gut and the brain (R).
- Cutting the vagus nerve, an important nerve that connects the gut with the brain (stem), substantially reduces risk of Parkinson’s disease in mice.
- According to Dr. Heiko Braak, alpha-synuclein aggregates already start low in the brain stem, and likely even in the gut, and then spread to higher regions, like the substantia nigra (R).
- Parkinson’s disease seems to spread anyhow further in the brain, from the midbrain regions, and then to other “higher” brain structures, like the cortex, which suggest that indeed the alpha-synuclein spreads from lower parts of the nervous centrum to higher parts, like a “prion”-like chain reaction.
Fig.: According to Braak’s hypotheses, Parkinson’s disease starts in the gut (enteric) nervous system and spreads “upwards” to the brain and then from lower to higher brain regions, finally reaching the neocortex.
“The Prion Hypothesis in Parkinson’s Disease: Braak to the Future.” Acta Neuropathologica Communications 1. CC BY 2.5
- Often, many years (or decades) before people get Parkinson’s disease these patients have gut problems, like constipation,
- In most Parkinson patients, the gut microbiome is dysregulated and unhealthy.
- The degree of presence of unhealthy gut bacteria (e.g. Enterobacteriaceae or Bacteroidetes) is associated with the severity of Parkinson’s symptoms in patients, such as gut difficulty or postural instability (R).
- The degree of absence of healthy gut bacteria (like Prevotellaceae) is also associated with severity of Parkinson’s symptoms in patients (R).
- Taking specific antibiotics (which might kill specific healthy gut bacteria) have been associated with an increased risk of Parkinson’s disease (R).
- In mice studies, antibiotic treatment (killing bacteria in the gut, including potential unhealthy bacteria that increase Parkinson’s symptoms) improves Parkinson symptoms.
- When Parkinson-prone mice (which overexpress alpha-synuclein) receive gut bacteria from Parkinson patients, their motor impairments significantly worsen compared to when they receive gut bacteria from healthy human donors (R).
- Adding alpha-synuclein aggregates (clumped-together alpha-synuclein proteins) into the intestines of mice causes behavioural problems and alpha-synuclein deposition in normal healthy mice, and degeneration of dopaminergic neurons in Parkinson-prone mice (R).
4. Oxidative damage
There is often increased oxidative damage in people with Parkinson’s disease.
This form of damage is caused by “free radicals”.
Free radicals are highly reactive small particles (like oxygen radicals) that steal electrons from other substances in our cell, thereby damaging them.
This “stealing of electrons” is called “oxidation”. Electrons function as the “glue” by which atoms are glued together, so stealing them can damage the atoms or molecules they are part of.
In Parkinson’s disease, neurons that produce dopamine suffer from a lot of oxidative damage. Dopamine is a messenger molecule that these neurons produce to communicate with each other. Dopamine is involved in movement, but also in motivation and pleasure.
Unfortunately, dopamine is a molecule that can get easily oxidized. This could help to explain why mainly dopaminergic neurons get so easily damaged by free radicals.
Also, mitochondria are very susceptible to oxidative damage. It could be that increased oxidative damage in the mitochondria further damages them. Mitochondrial dysfunction could also play 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 also cause oxidative damage in those brain regions.
Studies show an association between people living in agricultural areas where lots of pesticides are used and the risk of Parkinson’s disease (R,R,R).
5. Inflammation
Likely, inflammation is more a contributing factor to Parkinson’s disease than a primary cause.
Inflammation can increase the risk of Parkinson’s disease, or accelerate the disease.
Interestingly, some studies show that people who take anti-inflammatory drugs for a long time (for other reasons) 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 could damage neurons in the brain, including in the substantia nigra, the part of the brain where Parkinson’s disease likely 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.
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.
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.
Learn more about the genetic causes of Parkinson’s disease here.
