Jessica Madry

Introduction. On the global scale there is a prevalence of 100-300/100,000 people with Parkinson’s Disease (PD) and it is expected to double by 2030 due to the progressive aging of the world population¹. Parkinson’s Disease is a multi-systemic neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta^2,3. The misfolding/fibril forms of α-synuclein also demonstrate prion-like properties, including the capability to traverse synapses between susceptible neuron types, especially those that are weakly myelinated, which can induce Parkinson’s Disease^3,4. Studies have shown that performed fibril injection into the gut decreases dopaminergic neurons in a Parkinson’s Disease-like fashion⁴. The transmission of the pathological α-synuclein from the gut has shown to lead to motor and non- motor symptoms⁴. The future direction of investigation could suggest that age-related declines in protein homeostasis function to diminish protective measures against α-synuclein pathology and may potentially lead to a mechanism that can be targeted to prevent this pathology⁵. Methods. α-Synuclein purification and α- synuclein preformed fibril (PFF) preparation were done, then intestinal intramuscular α-synuclein PFF injection, vagotomies, and behavioral tests were performed⁴. Thioflavin T assay, transmission electron microscopy, and inoculation of α-synuclein PFFs into the mouse gastric wall were executed⁶. Histologic and immunohistochemical analysis were preformed to track progress of α-synuclein movement, and One-way ANOVA with Tukey’s post-hoc test was used for analysis^4,6. Latency time, probe trial session, Morris maze test, exploration time of objects, percentage of novel object recognition, and the novel object test were used for cognitive testing⁴. In one study a vector system was used to induce a rapid expression of GCase in a novel viral capsid⁵. The duodenal GCase expression was determined by a densitometry analysis of western blots⁵.  Results. PFF injected WT mice showed a decrease in cognitive function based on escape4. Performing a vagotomy and α-synuclein deficiency prevented the psychological deficits in PFF injected mice in the gut, supporting that the vagus nerve plays a role in the transfer⁴. GCase activity promotes the degradation of α- synuclein aggregates. Decreased GCase production exacerbated α-synuclein pathology in older mice compared to younger mice⁵. Conclusion. The results showed that α-synuclein can spread from the gut to the brain via the vagus nerve to induce PD. This can serve to accelerate studies toward a specific molecular pathway associated with PD in relation to the gut-to-brain transfer of pathologic α-synuclein and act as guidance toward new therapeutic discovery.

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4. Kim S, Kwon S-H, Kam T-I, et al. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease. Neuron. 2019;103(4). doi:10.1016/j.neuron.2019.05.035
5. Challis C, Hori A, Sampson TR, et Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nature Neuroscience. 2020/03/01 2020;23(3):327-336. doi:10.1038/s41593-020-0589-7
6. Uemura, N., Yagi, H., Uemura, M.T. et al. Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. Mol Neurodegeneration 13, 21 (2018). https://doi.org/10.1186/s13024-018-0257-5