P 20 Immune-mediated propagation of α-Synuclein from the brain to the periphery in a mouse model of Parkinson's disease. (May 2022) - McFleder, R.
Abstract : Introduction: Parkinson's disease (PD) is classically known for its characteristic motor symptoms of bradykinesia, rigidity, and tremor. However, this disease is riddled with an assortment of non-motor manifestations, such as constipation, which is actually one of the first symptoms that patients experience. Investigations in the intestines of PD patients, have revealed the presence of α-Synuclein (aSyn) accumulations similar to the detrimental aggregates found in the Substantia Nigra (SN) of patients' brains. Where these aggregates originate and how they propagate throughout the body, however, remains unclear. Recent focus on the immune system has revealed a role for immune cells in the neurodegeneration in PD. As these cells are capable of traveling throughout the body, they may be the key to aSyn propagation and PD development. Uncovering the role of the immune system in aSyn propagation is crucial for the development of interventions aimed at early treatment of PD. Objective: To test if expression of aSyn in the brain results in intestinal aSyn expression and inflammation in a mouse model of PD. Methods: We utilized a mouse model of PD, where an Adeno-associated Virus serotype 1/2 (AAV1/2), expressing a human mutated form of aSyn (haSyn) associated with familial PD, is injected into the SN of WT mice. The AAV1/2 leads to neuronal expression of the haSyn and PD-like motor dysfunction in mice. As a control, an equal amount of empty AAV (EV) was used. At different time points following injection, the brains and intestines were isolated and evaluated by either immunohistochemistry or flow cytometry. Results: Localized expression of haSyn in the brain, resulted in increased expression and accumulation of both endogenous aSyn and haSyn in the intestines of mice. This aSyn accumulation started as early as 1 week after viral injection and continued for up to 10 weeks. These aSyn-containing cells were associated with an increase in CD4+ and CD8+ T cells in both the intestines and the brains of the haSyn mice. Conclusions: aSyn can propagate from the brain to the gut and results in activation of intestinal T cells. This data provides new insight into the origination of PD and can therefore help guide studies focused on prevention and early treatment of PD.