Parkinson’s Disease: Neurons, Autoimmunity and Gut Infections, Oh My!

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by Angela Nelson

Parkinson’s disease (PD) is a neurodegenerative disease caused by the death of dopamine-producing cells – dopaminergic neurons – located in the substantia nigra, a small region of the brain (1). Dopamine (DA), sometimes known as “the feel-good hormone,” also has an important role in movement, memory, cognition, mood, behaviour, learning, and sleep (2). Without the ability to produce DA, Parkinson’s patients will experience motor difficulties, which can impact quality of life. Stiffness, tremors, poor balance and altered gait all indicate PD, but these symptoms only appear once more than half of dopaminergic neurons in the substantia nigra have degenerated (3). L-dopa (Levodopa) is the most commonly-prescribed drug to treat PD (4). It functions to replace the DA which the brain should be producing, thereby alleviating motor symptoms. However, DA substitutes do not halt or reverse disease progression (5). The ideal treatment would be preventative, meaning it would avert the loss of dopaminergic neurons, but this is rather challenging considering the cause of PD is still unknown. Unlike inherited diseases such as cystic fibrosis and Huntington’s disease, it isn’t as simple as adjusting your deerstalker cap and pulling from your pipe before pointing to a strange gene and exclaiming, “By Jove! There’s the scoundrel!”     

There is consensus among researchers, however, that dysfunction of the mitochondria – the powerhouse of the cell – plays a key role in the loss of dopaminergic neurons (6). PINK1 is a protein heavily involved with the mitochondria, and patients with early-onset PD have been found to have mutations in the genes which code for this protein (6). Researchers have tried using mice to model human PD but found few or no Parkinson-like symptoms in mice that had both mutations in PINK1 and a buildup of dysfunctional mitochondria. This indicates the onset of PD must be caused by other factors in addition to genetics (7). Surprisingly, the immune and digestive systems appear to be heavily implicated in this neural disease.

In 2019, researchers in Montreal, Canada provided evidence using murine (mouse) models that an intestinal infection could cause an autoimmune reaction which in turn triggers PD. Our immune system normally knows not to attack us by recognizing certain markers on our own body’s cells, called MHC-I. Cells can also use this marker to communicate to the immune system that something is wrong inside the cell, such as a viral infection. The cell will take a piece of the virus and put it on its marker, like waving a red flag for help, so immune cells can mount a response to eliminate the virus. PINK1 prevents the cell from doing the same thing with a piece of its own mitochondria (8). In cells without PINK1, a bacterial intestinal infection incites the cells to put bits of mitochondria on their MHC-I. The immune system is then programmed to attack its own mitochondria (8). What’s more, some of these mitochondria-hunting immune cells are localized in the mice’s brains (9).It remains to be proven in humans, but this autoimmune mechanism could account for the loss of dopaminergic neurons, eventually resulting in symptomatic PD.

A growing body of evidence is pointing to PD originating in the gut. Analysis of the gut microbial population of patients with PD showed they have a pattern of microorganisms that can trigger inflammation (an immune response) in the intestine, which is not seen in healthy volunteers (10). Moreover, several independent studies have shown that patients with inflammatory bowel diseases are at much higher risk of developing PD; one study determined 28% higher prevalence of PD in individuals with Crohn’s or ulcerative colitis than healthy individuals (11). Intestinal symptoms, such as constipation, often precede motor symptoms of the disease (12). This all indicates a strong correlation between bowel health and PD, but more research is required before this knowledge can be applied clinically.  With a better understanding of the role of the digestive system in PD, we can hopefully diagnose the disease earlier and eventually develop successful preventative therapies.

References

1. https://doi.org/10.1111/jnc.13731

2. https://www.news-medical.net/health/Dopamine-Functions.aspx

3. https://doi.org/10.1007/s12017-017-8454-x

4. http://parkinson.org/Understanding-Parkinsons/Treatment/Prescription-Medications/Levodopa

5. https://doi.org/10.5694/j.1326-5377.2010.tb03453.x

6. https://doi.org/10.1016/j.bbadis.2009.08.013

7. https://doi.org/10.3233/JPD-2011-11041

8. https://doi.org/10.1016/j.cell.2016.05.039

9. https://doi.org/10.1038/s41586-019-1405-y

10. https://doi.org/10.1007/s10517-017-3700-7

11. https://www.scientificamerican.com/article/does-parkinsons-begin-in-the-gut/

12. https://doi.org/10.1016/S1474-4422(09)70068-7

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