2023-08-22 14:54:23
The increasing evidence of enteric symptoms related to Parkinson’s disease has led to suspicion of its intestinal origin. An experiment live suggests that the pathology is triggered by an autoimmune reaction in the intestines — years before the first movement disorders appeared. These results strengthen the prospects for early diagnosis to potentially stop the disease in its tracks.
In view of the glaring motor symptoms — resulting from the loss of dopaminergic neurons — scientists have long assumed that Parkinson’s disease is triggered first in the brain. However, its pathogenesis begins long before the diagnosis and the neuronal loss would appear only at the advanced stage of the pathology. On the other hand, enteric symptoms are frequently observed in its early stage. Constipation, for example, is a symptom reported in 70% of patients up to 20 years before the appearance of the first motor symptoms.
Despite growing evidence for the involvement of the enteric nervous system in a wide range of neurodegenerative diseases, the mechanisms underlying this correlation remain poorly understood. Indeed, there is significant heterogeneity in the hypotheses suggested. While some evoke a microbiotic origin, others lean more towards an autoimmune origin. The new study, led by researchers at Columbia University, supports the latter hypothesis, showing evidence of enteric autoimmune reactions in mouse models of the disease.
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Illustration summarizing the results of the study. © Francesca Garetti et al.
A partially autoimmune disease
One of the main characteristics of Parkinson’s disease is the aggregation of the protein alpha-synuclein inside neurons, which, by folding up abnormally, becomes toxic and leads to their death. The experts of the new study, detailed in the specialized journal Neuron, found that the misfolded protein might also invade the extracellular medium. This presence outside the neurons is likely to trigger an immune response and cause greater inflammatory damage than the internal accumulation of the protein.
Namely that the blood of people suffering from Parkinson’s has a high level of immune cells specific to the nervous system, “but it is not known where or when they are initiated”, indicates in a communiqué the study’s lead author, David Sulzer of Columbia University. With his team, he believes that this reaction begins in the first place in the intestine. This hypothesis is consistent with previous epidemiological research, indicating a close correlation between intestinal inflammation and early stages of the disease. It is suggested that this pathogenicity reaction then spreads to the brain, ascending via the vagus nerve.
An autoimmune reaction in mice to a protein involved in Parkinson’s disease here damaged neurons in the gastrointestinal tract, supporting the hypothesis that the disease begins in the intestines. © David Sulze
In order to test their hypothesis, the Columbia researchers genetically modified mice so that they present abnormal aggregations of alpha-synuclein outside their neurons, at the level of the brain and the intestine. The presence of the toxic proteins in the gut has been found to trigger an autoimmune response, inducing the inflammation that causes the gastrointestinal symptoms commonly seen in most early-stage patients (such as constipation) . ”
This shows that an autoimmune reaction can lead to what appears to be the early stages of Parkinson’s disease and confirms that Parkinson’s disease is partly autoimmune.
“says Sulzer.
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These results confirm that inflammation of the peripheral nervous system (connecting the brain and spinal cord to the gut and other internal organs) is most likely involved in the pathogenicity of Parkinson’s. On the other hand, elevated levels of proinflammatory cytokines and circulating CD4+-expressing T cells were detected in early-stage patients. These lymphocytes specifically recognize neo-epitopes derived from alpha-synuclein. Neoepitopes are recognized by the immune system as targets for T cells and can trigger a response. More specifically, α-syn 32-46, one of these neoepitopes, binds with high affinity to the HLA-DRB1∗15:01 gene, involved in autoimmune diseases.
Injecting α-syn 32-46 into mice expressing human HLA-DRB1∗15:01 triggers gut inflammation and causes loss of dopamine enteric neurons, constipation, and weight loss — according to researchers at the study. The injection also activated genetic signatures of innate and adaptive immunity in the gut and induced changes in CD4+ T cells.
On the other hand, no notable response was detected at the level of the brain during the experiment in mice. The research team believes that due to their young age, their blood-brain barrier is not yet weakened enough to allow immune cells to pass through. This is probably the reason why the disease progresses with aging and why older patients develop both gastrointestinal and neurological symptoms. However, more research is needed to truly confirm this hypothesis.
Source : Neuron
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