Inflammation plays an important role in Parkinson’s disease.
Inflammation happening in the brain (“neuroinflammation”) damages neurons and can lead to neuronal cell death.
Neuroinflammation involves the activation of the brain’s resident immune cells: microglia and astrocytes, while there can also be an influx of immune cells from the blood into the brain.
- Microglia, often referred to as the brain’s resident macrophages (immune cells), continuously survey the brain for signs of insult or injury. These cells perform essential housekeeping functions, clearing cellular debris and supporting neuronal health. However, in Parkinson’s disease, microglia can become chronically activated, secreting pro-inflammatory substances (cytokines) and free radicals that damage neurons.
- Astrocytes, a type of support cell found in the brain, can also contribute to inflammation by releasing inflammatory mediators, further amplifying a neurotoxic microenvironment.
- Other immune cells: specific immune cells present in the blood (such as lymphocytes) can also enter the brain and damage brain cells.
Why do these cells become activated?
Alpha-Synuclein Activating Microglia
In Parkinson’s disease, a specific protein tends to aggregate and accumulate in the brain, called alpha-synuclein.
Misfolded alpha-synuclein aggregates are believed to act as a potent immunological trigger.
Experimental models have shown that microglial cells (brain immune cells) exposed to alpha-synuclein release levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6).
These mediators, in turn, can lead to increased oxidative stress and further damage to dopaminergic neurons in the substantia nigra in the brain.
Over time, chronic activation of microglia can cause a self-perpetuating cycle of inflammation and neuronal injury:
Damaged neurons release alpha-synuclein into the extracellular space, further stimulating microglia. Meanwhile, inflammatory mediators damage more neurons, releasing more alpha-synuclein, fueling a vicious cycle.
The Gut-Brain Axis
The gut also impacts the brain.
Our gut harbors a complex ecosystem of bacteria that modulate immune responses. Disruptions in the gut microbiota (dysbiosis) have been linked with increased inflammation, increased intestinal permeability (“leaky gut”), and systemic immune activation.
For example, in Parkinson’s patients, specific unhealthy bacteria secrete substances that leak from the gut into the bloodstream, reaching the brain and causing inflammation in the brain.
Furthermore, alpha-synuclein aggregates have been detected in the nervous system of the gut in Parkinson’s patients, sometimes years before the onset of motor symptoms.
Learn more about the role of the gut in Parkinson's disease here.
Unhealthy Mitochondria
In Parkinson’s disease, the mitochondria get damaged. Mitochondria are the power plants of the cells, generating energy for our cells.
However, when mitochondria are damaged, they secrete substances that increase inflammation in the cell and in surrounding cells.
Genetic Factors Shaping Inflammatory Responses
Genetics could also play a role in modulating inflammatory pathways involved in Parkinson’s disease.
Mutations in genes such as LRRK2 (leucine-rich repeat kinase 2), PARK7 (DJ-1), and PINK1 have been implicated in familial and sporadic forms of Parkinson’s disease.
Interestingly, LRRK2 mutations are associated not only with Parkinson’s disease, but also with inflammatory bowel disease (e.g. ulcerative colitis or Crohn’s disease), suggesting a shared immune-related mechanism.
Moreover, specific genetic variants encoding for immune receptors on immune cells (major histocompatibility complex or MHC), which is central to immune surveillance, have also been linked to Parkinson’s disease risk (and increased risk of auto-immune diseases like Crohn’s disease).
Other factors
Some studies have found an association between the use of anti-inflammatory drugs and reduced risk of Parkinson’s disease (however, often, these drugs come along with serious side-effects) (R).
Unhealthy foods and diets can also increase inflammation in the brain. For example, high peaks of glucose cause glucotoxicity and advanced glycation end products (AGEs), causing inflammation. Various unhealthy fats can also cause inflammation of the brain.
Healthy diets, on the other hand, contain substances that reduce inflammation (learn more about the best foods for Parkinson’s disease here).
Conclusion
Parkinson’s disease remains a complex, multifactorial disorder.
Alpha-synuclein pathology, mitochondrial dysfunction, genetic predisposition and many other mechanisms fuel chronic inflammation, which damages brain cells, especially the cells in the substantia nigra, which are most affected in Parkinson’s disease.
It could be that inflammation plays more a secondary role in the disease, in the sense that increased inflammation is not a root cause of Parkinson’s disease, but could drive - or increase the risk of - Parkinson’s disease.
While anti-inflammatory therapies and immunomodulatory approaches are promising areas to treat or prevent Parkinson’s disease, clinicians must balance the need to dampen harmful inflammation without compromising beneficial immune responses crucial for clearing misfolded proteins and combating infections.
A more refined understanding of the timing and nature of inflammatory processes in Parkinson’s disease - particularly early in the disease - could help guide more targeted interventions.
Interestingly, various foods can reduce inflammation in the body and the brain, and have been associated with a reduced risk and progression of Parkinson’s disease.
