Mutant LRRK2 exacerbates immune response and neurodegeneration in a chronic model of experimental colitis

• Published in: Acta neuropathologica 2023-08, Vol.146 (2), p.245-261
• Main Authors: Cabezudo, Diego, Tsafaras, George, Van Acker, Eva, Van den Haute, Chris, Baekelandt, Veerle
• Format: Article
• Language: English
• Subjects: Analysis; Animals; B cells; Bone marrow; Colitis; Colitis - chemically induced; Colitis - genetics; Dextran; Digestive system; Dopamine receptors; Ethylenediaminetetraacetic acid; Gastrointestinal diseases; Gastrointestinal tract; Homeostasis; Immune response; Immunity; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - genetics; Kinases; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; LRRK2 protein; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Movement disorders; Mutants; Mutation - genetics; Neurodegeneration; Neurodegenerative diseases; Neurosciences; Original Paper; Parkinson Disease - pathology; Parkinson's disease; Pathology; Phenotypes; Risk factors; Substantia nigra; Synuclein; Transplantation
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-023-02595-9

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.