Objective: To test the hypothesis the neurodegenerative cascade in the CNS that leads to Parkinson’s disease (PD) is initiated by signals emanating from the peripheral immune system.

Background: A number of loci have been shown to contribute to the development of PD, including several within LRRK2. Despite intensive research and an understanding of the abnormal signaling induced by LRRK2 mutations, the downstream processes that underlie LRRK2-mediated PD remain undetermined. One clue resides in the finding that LRRK2 mutations appear to increase the pathogenicity of exogenous insult(s). Recently, we showed that R1441G and G2019S mutations in LRRK2 affect the functional crosstalk between the peripheral immune system and microglia within the CNS’ innate immune system. This alteration appears to mediate both inflammation in the SNpc and degeneration of its DA neurons. Based on this data, we hypothesized that the neuroinflammation in LRRK2 mice following an exogenous insult did not initiate by a direct effect on microglia, but were triggered by dysregulated expression of circulating inflammatory cytokines/chemokines released by peripheral immune cells.

Method: Using bone marrow transplantation we generated chimeric mice whose immune system contains wt LRRK2 T- and B-cells, but whose CNS contains neurons, astrocytes and microglia that harbored mutant LRRK2 (either G2019S and R1441G). We next used these mice to determine if the replacement of mutant LRRK2 with wt LRRK2 in peripheral T- and B-cells diminished the neuroinflammatory response to LPS and rescued the SNpc DA cell loss induced in mutant LRRK2 mice.

Results: We found that chimeric mice with wt bone marrow transplanted into LRRK2 mice exhibited a wt response to LPS. Additionally, we demonstrated that these mice did not develop the LPS-induced SNpc DA cell seen in intact LRRK2 mice.

Conclusion: Our data suggest that the neuropathology seen in some cases of LRRK2-mediated PD may result from abnormal signals arising in the peripheral immune system rather than from a direct effect of LRRK2 in the CNS. This finding supports a paradigm shift in our understanding of the etiology of PD, as well as provide new targets for the treatment (and possibly prevention) of PD. Currently, we are using cre/loxP mouse models, to determine which peripheral immune cell is responsible for the inflammatory signals into the brain.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-peripheral-t-and-b-lymphocytes-in-lrrk2-mediated-parkinsons-disease/