A study published in Cell Reports has found α-synuclein, the fundamental protein of Parkinson’s disease, to be critical in immune function.
The gut-brain axis as a channel for disease
Parkinson’s disease, which causes damage to the portion of the brain responsible for movement, is widely known to be caused by the aggregation of α-synuclein. This protein is produced naturally by multiple tissues, including the peripheral and central nervous systems [1].
A few years ago, one study revealed that long before Parkinson’s manifests itself in the brain, the a-synuclein protein causes constipation as a result of damage to the enteric nervous system (ENS), which is responsible for the smooth functioning of the gastrointestinal system [2]. Other, similarly recent, studies have found that α-synuclein is taken up through the central nervous system, traveling through the vagus nerve and ultimately into the brain [3,4].
A protein with a reason to exist
In its natural form, this protein is neither an unwanted byproduct nor a consequence of malfunctioning protein production. Instead, it is produced by healthy, normally functioning cells, and it has been shown to be have an inflammatory effect in a previous in vitro study, attracting both human and murine neutrophils [5].
For this study, the researchers decided to take these results further by analyzing its effects in vivo. When a bacterial toxin was introduced into their intestines, mice that were genetically engineered to produce additional a-synuclein showed a much more robust immune response than mice that were engineered to produce none.
Whether examined 4 hours or 24 hours after the irritant was administered, multiple types of immune cells, along with the inflammatory factors IL-1ß and TNFα, were found in far greater quantities in the mice that produced α-synuclein. Similarly, mice with α-synuclein were also shown to better detect potential threats and fight them, recruiting more immune cells to where they were needed. In total, mice that did not produce α-synuclein had a fundamental immune system deficiency compared to mice that did.
In line with the murine results, α-synuclein was shown to drive macrophages towards the M1 (inflammatory) type in vitro. It was shown to drive the maturation of dendritic cells, the immune cells responsible for detecting antigens, and stimulated the production and differentiation of CD4+ T cells.
Conclusion
This study illustrates one of the downsides of biology research: there are very few things that are entirely bad and need to be removed completely. While this protein is the driver of Parkinson’s disease and obviously drives inflammation, its inflammatory quality is what makes it so necessary in the immune system. It is reasonable to believe that any compound that destroys α-synuclein entirely would also have a side effect of placing people at greater risk of contracting deadly infectious diseases.
Instead, just as we need to be able to modulate inflammatory responses as a whole in order to ameliorate the age-related increase in inflammation known as inflammaging, discovering a way to modulate α-synuclein in particular would potentially allow us to reduce unwanted gut inflammation, prevent damage to the enteric nervous system, and stop Parkinson’s disease before it starts.
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Literature
[1] Bartels, T., Choi, J. G., & Selkoe, D. J. (2011). a-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature, 477(7362), 107-110.
[2] Rota, L., Pellegrini, C., Benvenuti, L., Antonioli, L., Fornai, M., Blandizzi, C., … & Colla, E. (2019). Constipation, deficit in colon contractions and alpha-synuclein inclusions within the colon precede motor abnormalities and neurodegeneration in the central nervous system in a mouse model of alpha-synucleinopathy. Translational neurodegeneration, 8(1), 1-15.
[3] Breit, S., Kupferberg, A., Rogler, G., & Hasler, G. (2018). Vagus nerve as modulator of the brain–gut axis in psychiatric and inflammatory disorders. Frontiers in psychiatry, 9, 44.
[4] Kim, S., Kwon, S. H., Kam, T. I., Panicker, N., Karuppagounder, S. S., Lee, S., … & Ko, H. S. (2019). Transneuronal propagation of pathologic a-synuclein from the gut to the brain models Parkinson’s disease. Neuron, 103(4), 627-641.
[5] Stolzenberg, E., Berry, D., Yang, D. E., Lee, E. Y., Kroemer, A., Kaufman, S., … & Zasloff, M. A. (2017). A role for neuronal alpha-synuclein in gastrointestinal immunity. Journal of innate immunity, 9(5), 456-463.
View the article at lifespan.io
