By the time patients with Parkinson’s disease notice tremors and visit neurologists, the disease has progressed into their central nervous systems. Gut-related symptoms, such as constipation and weight loss resulting from the loss of enteric neurons—a hallmark of Parkinson’s disease—can appear 20 years prior to severe neurological symptoms, but why the neurons die is not clear.1 In a recent study published in Neuron, scientists reported that CD4 T cells in the gut drive enteric neuron loss by attacking alpha-synuclein, the protein that aggregates in the brains of people with Parkinson’s disease.2 These findings could pave the way for early detection of Parkinson’s disease and development of immunotherapies.
“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 idea of Parkinson’s disease originating in the gut, known as the Braak hypothesis, has been around since the late 1990s, when neurologists Heiko Braak and Kelly Del Tredici from the University of Ulm, categorized the progression of Parkinson's disease from other organs into the brain based on the distribution of alpha-synuclein aggregates in the postmortem brain tissues of people with Parkinson’s disease.3,4
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.5 “That was seen as a very interesting finding,” said Fasano.
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Sulzer decided to investigate this connection further using mice with humanized immune systems. These mice expressed the human leukocyte antigen (HLA) allele (DRB1*15:01) instead of the mouse version of the same allele, which codes for the proteins that display foreign antigens on the surfaces of infected cells. He injected them with the reactive alpha-synuclein fragment and monitored their weight and gastrointestinal (GI) transit times by orally administering a nonabsorbable red dye with food and measuring the time until excretion. Compared to mice that did not receive the human alleles or did not receive alpha-synuclein injections, the HLA mice became sick, looked hunched and ruffled, and had markedly longer GI transit times at 22 days after immunization. Sulzer and his team categorized mice as sick if they lost at least 12 percent of their initial weight.
“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.
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.
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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.
- Khoo TK, et al. The spectrum of nonmotor symptoms in early Parkinson disease. Neurology. 2013;80(3):276-281.
- 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.
- Braak H, Del Tredici K. Nervous system pathology in sporadic Parkinson disease. Neurology. 2008;70(20):1916-1925.
- Mezey E, et al. Alpha synuclein is present in Lewy bodies in sporadic Parkinson’s disease. Mol Psychiatry. 1998;3:493-499.
- Sulzer D, et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature. 2017;546:656-661.
