Mutations in a number of genes contribute to development of Parkinson's disease (PD), including several within the LRRK2 gene. However, little is known about the signals that underlie LRRK2-mediated neuronal loss. One clue resides in the finding that the neurodegenerative cascades emanate from signals arising from the peripheral immune system. Here, using two chimeric mouse models, we demonstrate that: 1) the replacement of mutant LRRK2 with wt form of the protein in T- and B-lymphocytes diminishes LPS-mediated inflammation and rescues the SNpc DA neuron loss in the mutant LRRK2 brain; 2) the presence of G2019S or R1441G LRRK2 mutation in lymphocytes alone is sufficient for LPS-induced DA neuron loss in the genotypically wt brain; and 3) neutralization of peripheral IL-6 overproduction prevents the SNpc DA neuron loss in LPS-treated mutant LRRK2 mice. These results represent a major paradigm shift in our understanding of PD pathogenesis and suggest that immune dysfunction in some forms of familial PD may have primacy over the CNS as the initiating site of the disorder.
© 2022. The Author(s).