Uneasy Thoughts Regarding Parkinson’s Disease

Early Parkinson disease symptoms are mediated by CD4 T lymphocytes in the gastrointestinal tract.

Parkinson’s patients contact neurologists when they have tremors, but by then the disease has spread to their central nervous systems. Parkinson’s disease is characterized by gut-related symptoms, such as weight loss and constipation, which can occur 20 years before serious neurological symptoms. The reason for the death of the enteric neurons is unknown.1. According to a recent study that was published in Neuron, enteric neuron loss is caused by CD4 T lymphocytes in the gut targeting alpha-synuclein, a protein that clumps in Parkinson’s disease patients’ brains.2. The development of immunotherapies and early Parkinson’s disease diagnosis may be facilitated by these discoveries.

“This study seems to indicate that there is a window of intervention very early that can involve modulation of the immune system,” said Alfonso Fasano, a neurologist at the University of Toronto who was not involved in the study. He noted, however, that since Parkinson’s disease is not seen as an autoimmune disease, it’s not obvious how researchers could do that.

The Braak hypothesis, which dates back to the late 1990s, postulates that Parkinson’s disease originated in the gut. This theory was developed by neurologists Heiko Braak and Kelly Del Tredici of the University of Ulm, who classified the disease’s progression from other organs into the brain by looking at the distribution of alpha-synuclein aggregates in the postmortem brain tissues of Parkinson’s disease patients.

David Sulzer, a neuroscientist at Columbia University and a coauthor of this study, wanted to further investigate the connection between aggregated alpha-synuclein and Parkinson’s disease. A few years ago, he found that immune systems (predominantly CD4 T cells) from people with Parkinson’s disease reacted strongly to a fragment of alpha-synuclein. “That was seen as a very interesting finding,” said Fasano.

Sulzer made the decision to use mice with humanized immune systems to look at this relationship in more detail. Rather than expressing the mouse version of the same allele that codes for the proteins that show foreign antigens on the surfaces of infected cells, these mice displayed the human leukocyte antigen (HLA) allele (DRB1*15:01). He gave them the reactive alpha-synuclein fragment by injection, and then he measured the time till excretion and tracked their weight and gastrointestinal (GI) transit times by giving them a nonabsorbable red dye to eat. In contrast to mice that were neither given the human alleles or administered alpha-synuclein injections, the HLA animals developed illness, exhibited a slumped and disheveled appearance, and had significantly prolonged gastrointestinal transit times 22 days following inoculation. Sulzer and his colleagues classified mice as ill if at least 12 percent of their starting weight was shed.

“We didn’t get Parkinson’s disease in the brain,” said Sulzer. “But we did get something that looks very much like Parkinson’s disease in the gut.”

Next, they wanted to quantify the loss of enteric neurons, so they fluorescently labeled the antineuronal nuclear antibody type 1 (ANNA1) and tyrosine hydroxylase (TH) proteins. “All of the enteric neurons, to my knowledge, express ANNA1 in the nucleus, but only the dopamine neurons, which are a small fraction of the total number of neurons, have tyrosine hydroxylase,” Sulzer explained.

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Loss of enteric neurons after immunization strongly correlated with peak weight loss and longest GI transit times, and the loss of TH+ dopamine neurons continued even after improvement in other symptoms. Sulzer then analyzed the submucosal gut tissue for signs of T cell-specific transcriptomic activity and found the T cells as activated immune cells in the gut, where they caused inflammation in response to alpha-synuclein.

Lastly, to confirm which T cells were responsible for the damage, the researchers depleted T cells in the mice. They found that depleting the CD8 T cells had no effect on the symptoms. Depleting the CD4 cells only partially improved the symptoms, implicating the CD4 cells but also indicating that multiple types of T cells in the gut were responsible for the damage since the mice did not fully recover after depletion. Investigating all of the causative cell types is tricky because the intestines are incredibly long organs, explained Sulzer. “To really study that whole tissue is an immense undertaking,” he said.

He further emphasized that it is more important for them to figure out why injecting alpha-synuclein only gave the mice the initial gut symptoms but not full-blown Parkinson’s disease. Now, he and his team want to find the missing link between the gut and the neurological symptoms of the disease to pinpoint the most effective stage for intervention. “To us, that seems to be the central question,” he said.

This news is a creative derivative product from articles published in famous peer-reviewed journals and Govt reports:

1. Khoo TK, et al. The spectrum of nonmotor symptoms in early Parkinson disease. Neurology. 2013;80(3):276-281.
2. Garretti F, et al. Interaction of an α-synuclein epitope with HLA-DRB1∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease. Neuron. 2023;111(21):3397-3413.
3. Braak H, Del Tredici K. Nervous system pathology in sporadic Parkinson disease. Neurology. 2008;70(20):1916-1925.
4. Mezey E, et al. Alpha synuclein is present in Lewy bodies in sporadic Parkinson’s disease. Mol Psychiatry. 1998;3:493-499.
5. Sulzer D, et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature. 2017;546:656-661.

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