In a mouse DSS-colitis model, intestinal inflammation drives neuroinflammation and nigrostriatal pathology across genotypes, and these effects occur independently of Lrrk2 G2019S kinase activation.

Reinforces the gut–brain axis as a contributor to PD-relevant pathology and implies that targeting peripheral intestinal inflammation (or patient stratification by inflammatory status) may be a more promising therapeutic or preventative approach than relying solely on LRRK2 kinase inhibition for…

INTRODUCTION: The pathogenesis of Parkinson's disease (PD) has been linked to environmental factors, toxins, genetics, and peripheral inflammation. Importantly, intestinal inflammation like that seen in Crohn's disease (CD) or food allergies has been implicated in risk for neurodegeneration and late-onset PD. Further, CD and PD share genetic risk factors including gain-of-function leucine-rich repeat kinase 2 (LRRK2) mutations. Here, we aim to better understand how intestinal inflammation synergizes with Lrrk2 levels or kinase activation to promote neurodegeneration in young and old mice. METHODS: We utilized bacterial artificial chromosome (BAC) mice overexpressing wildtype mouse Lrrk2 or mutant G2019S mouse Lrrk2 and compared them with C57B6J mice at baseline and under conditions of intestinal inflammation using dextran sodium sulfate (DSS) colitis models. RESULTS: While our data revealed regulation of the brain inflammatory state by Lrrk2, we did not observe age-dependent selective vulnerability or protection in Lrrk2 mouse lines in colitis protocols. Instead, DSS phenotypes were associated with increased nigrostriatal dysregulation in all genotypes independent of age. DISCUSSION: While Lrrk2 mutations appear to influence the genesis of peripheral inflammation, our data suggest that Lrrk2 activation due to a gain-of-function mutation does not exacerbate the effects of inflammation on nigrostriatal degeneration in this model.