The link between the gut and the brain in
Parkinson's disease (PD) pathogenesis is currently a subject of intense research. Indeed, gastrointestinal dysfunction is known as an early symptom in PD and
inflammatory bowel disease (IBD) has recently been recognised as a risk factor for PD. The
leucine-rich repeat
kinase 2 (LRRK2) is a PD- and IBD-related
protein with highest expression in immune cells. In this study, we provide evidence for a central role of LRRK2 in gut
inflammation and PD. The presence of the gain-of-function G2019S mutation significantly increases the disease phenotype and inflammatory response in a mouse model of experimental
colitis based on chronic
dextran sulphate sodium (DSS) administration.
Bone marrow transplantation of wild-type cells into G2019S knock-in mice fully rescued this exacerbated response, proving the key role of mutant LRRK2 in immune cells in this experimental
colitis model. Furthermore, partial pharmacological inhibition of LRRK2
kinase activity also reduced the
colitis phenotype and
inflammation. Moreover, chronic experimental
colitis also induced
neuroinflammation and infiltration of peripheral immune cells into the brain of G2019S knock-in mice. Finally, combination of experimental
colitis with overexpression of α-
synuclein in the substantia nigra aggravated motor deficits and dopaminergic neurodegeneration in G2019S knock-in mice. Taken together, our results link LRRK2 with the immune response in
colitis and provide evidence that gut
inflammation can impact brain homeostasis and contribute to neurodegeneration in PD.