Mutant LRRK2 in lymphocytes regulates neurodegeneration via IL-6 in an inflammatory model of Parkinson\u2019s disease

Elena Kozina,Matthew Byrne,Richard Jay Smeyne

doi:10.1038/s41531-022-00289-9

Elena Kozina, Matthew Byrne + Show 1 more

Open Access

https://doi.org/10.1038/s41531-022-00289-9

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Abstract

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.

Highlights

Parkinson’s disease (PD), the second most common neurodegenerative disorder, is a major public health predicament affecting over 6 million people[1] with estimates that this number will rise to 12 million by 20402
We found that the exacerbated neuroinflammation and substantia nigra pars compacta (SNpc) DA cell loss do not depend on the active participation of the brain resident microglia or infiltrating T-cells and/or monocytes, but are likely mediated by circulating inflammatory molecules that are dysregulated by mutant LRRK237
We propose that the neurodegenerative cascades in PD emanate from signals arising from the peripheral immune system and that LRRK2-PD is primarily an immune disorder, with secondary effects manifested in the CNS

Summary

Introduction

Parkinson’s disease (PD), the second most common neurodegenerative disorder, is a major public health predicament affecting over 6 million people[1] with estimates that this number will rise to 12 million by 20402. Recent evidence from clinical and experimental studies suggests an influential, yet largely underappreciated, force in PD pathogenesis, that of immune signals originating outside the brain. Numerous human studies over the past years have reported alterations in cytokines in PD patients biofluids (both, serum and CSF)[11], impaired monocytes phagocytic activity[12], a distinct transcriptomic profile of peripheral monocytes[13], an unbalance in Th cells toward the pro-inflammatory phenotypes[14], decrease in Treg ability to suppress the activity of Teff cells[15–17] and the presence of α-synuclein reactive T-cells in the blood of newly diagnosed PD patients[18]. Recent studies demonstrated increased levels of endotoxin in PD patients’ blood, especially those with a higher risk for dementia, as well as greater gastrointestinal permeability with lower levels of LPS-binding protein and increased gut staining for E. coli suggesting an active role for bacterial infection in the outcome of the disease[23,24]. It is proposed that the immune component in PD occurs early and changes dynamically with the disease progression, contributing to the neuronal loss observed in patients

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