A new study in mice shows how the immune system may play a role in the early gastrointestinal symptoms of Parkinson’s disease, decades before movement problems develop.
Researchers found that injecting a specific piece of the alpha-synuclein protein into genetically modified mice triggered inflammation and loss of nerve cells in the gut, leading to constipation and weight loss.
This mimics the digestive issues that are often the first warning signs of Parkinson’s in people.
The study highlights the importance of the immune system and gut-brain connection in the early stages of Parkinson’s disease.
Key points:
- Researchers injected part of the alpha-synuclein protein called “a-syn 32-46” into mice. This piece of the protein can trigger an immune response in people who have a specific gene called HLA-DRB1*15:01.
- The genetically modified mice lacked their normal immune genes and instead had the human HLA-DRB1*15:01 gene.
- After injection with a-syn 32-46, these mice developed severe constipation, weight loss, and loss of nerve cells in the gut. This mimics early Parkinson’s symptoms seen in people.
- In contrast, normal mice injected with a-syn 32-46 did not develop these issues, showing the reaction required both the protein fragment and human gene.
- Analyses of the mouse gut tissue revealed inflammation and immune cell changes similar to those seen in inflammatory bowel disease.
- Depleting CD4+ immune cells in the mice prevented the loss of gut dopamine neurons, implicating the immune system’s involvement.
- No inflammation or neuron loss was seen in the brain, suggesting additional factors are required to spread to the central nervous system.
Source: Neuron. 2023 Aug 11.
The Gut-Brain Connection in Parkinson’s Disease
Parkinson’s disease involves the loss of dopamine-producing nerve cells in the brain region that controls movement.
This causes motor symptoms like tremor, stiffness, and slow movement.
However, the disease process is thought to start years or even decades earlier in the nerves of the gut.
In fact, gastrointestinal issues like constipation are often one of the first symptoms of Parkinson’s, arising 10-20 years before the motor problems that lead to diagnosis.
This reflects early damage to the intricate network of nerves in the digestive system, called the enteric nervous system.
The enteric nervous system contains millions of nerve cells that line the digestive tract and coordinate processes like motility and secretion.
Loss of these important gut neurons is believed to contribute to the digestive issues seen in early Parkinson’s.
The vagus nerve provides a direct connection between gut nerves and dopamine-producing neurons in the brain.
So Parkinson’s may start in the gut and travel to the brain via this pathway.
This is known as the “gut-brain axis” and is an area of increasing focus for understanding Parkinson’s onset and progression.
The Immune System’s Role in Parkinson’s
In addition to the gut-brain connection, researchers have long suspected the immune system is involved in Parkinson’s disease.
People with Parkinson’s have higher levels of inflammation and certain profiles of immune cells and proteins.
This study provides evidence that the immune system can drive the loss of gut neurons and GI symptoms associated with early Parkinson’s.
The researchers focused on a specific fragment of the alpha-synuclein protein called “a-syn 32-46.”
Alpha-synuclein builds up in the brains of Parkinson’s patients and is a major component of the cellular clumps known as Lewy bodies that are the hallmark of the disease.
Previous work found some Parkinson’s patients have immune cells that specifically target and react to the a-syn 32-46 fragment.
This immune response is most common in people who have a gene called HLA-DRB1*15:01.
By injecting mice with both the human gene and the a-syn protein fragment, the researchers essentially recreated this immune reaction seen in some Parkinson’s patients.
The genetically modified mice developed digestive symptoms and nerve cell damage that mirrors early Parkinson’s disease.
Important immune cells called CD4+ T cells were found to drive the loss of dopamine-producing neurons in the gut. Depleting CD4+ cells prevented the nerve cell death.
No inflammation or neuron loss occurred in the brain, suggesting additional factors are required for the disease to spread from gut to brain.
But the findings shed light on the immune system’s potential role in initiating the gut issues that precede Parkinson’s diagnosis.
Translating Mouse Findings to Humans
Animal research always requires cautious interpretation when applying results to humans.
But studying mice allows researchers to probe cellular and molecular processes not easily examined in people.
As described, this study mirrored specific immune interactions thought to occur in a subset of Parkinson’s patients who carry the HLA-DRB1*15:01 gene.
The mice developed digestive symptoms and nerve damage similar to those seen in early Parkinson’s disease.
By tracking changes in gut tissues over time, the study provides clues to the sequence of events:
- Injection of the a-syn protein fragment triggered activation of various immune cells and inflammatory responses in the gut.
- Inflammation preceded the loss of gut neurons, implicating the immune reaction in nerve damage.
- Early loss of neurons was followed by progressive degeneration of dopamine-releasing nerve fibers.
- Digestive symptoms arose alongside inflammation and neuron loss, then improved as mice recovered, similar to the waxing and waning of gastro issues in Parkinson’s.
While future studies are needed to confirm the mechanisms, the findings suggest strategies to block these inflammatory immune responses may protect gut neurons and reduce digestive symptoms in early Parkinson’s.
The research also highlights the need to better understand the gut-brain connection in Parkinson’s progression.
What additional factors allow the disease to spread from the enteric nervous system to the brain?
Answering this could unveil new treatment targets to prevent worsening motor impairment.
Ongoing Research: Immune system, gut-brain, Parkinson’s disease
This study provides another piece of the Parkinson’s puzzle by implicating the immune system and gut-brain connection in early non-motor symptoms.
Ongoing research aims to further untangle:
- How inflammation drives the loss of gut neurons
- The sequence of events that allows pathology to ascend from the gut to the brain
- Factors that lead to aggregation of the alpha-synuclein protein
- The role of genetics and other risk factors in disease onset and progression
A clearer picture of the cellular processes underlying Parkinson’s onset and progression will help identify new biomarkers for early diagnosis and intervention.
More personalized treatments tailored to individual risk factors may someday help prevent or slow Parkinson’s disease.
References
- Study: Interaction of an a-synuclein epitope with HLA-DRB1*15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease
- Authors: Francesca Garretti et al. (2023)
