George T. Kannarkat, United States of America
Emory University PhysiologyAuthor Of 1 Presentation
EXPERIMENTAL COLITIS PROMOTES SUSTAINED CD8 TCELL-DEPENDENT NEUROINFLAMMATION AND PARKINSONIAN NEUROPATHOLOGY IN MICE
Abstract
Aims
Genetic and epidemiological evidence implicate inflammatory bowel disease in Parkinson's disease risk. We sought to investigate similarities between IBD and PD using human blood and colonic biopsy samples and the direct effects of gut inflammation on dopaminergic neurodegeneration in mice.
Methods
We used biochemical and immunological approaches to interrogate IBD and PD patient blood and colonic biopsies and used a mouse model of experimental colitis to investigate the extent of dysfunction induced in dopaminergic neurons in the brain and the mechanisms involved.
Results
We found high levels of NFκB p65 in colonic biopsies and other inflammatory mediators and reduced levels of Regulator of G-Protein Signaling-10 (RGS10) – a GAP identified previously by our group as a negative regulator of NFκB in myeloid cells. To evaluate directly whether this inflammatory profile could impact and/or increase vulnerability of dopaminergic pathways, we employed a RGS10-null mouse model challenged with experimental colitis. In male mice, colitis caused sustained CD8+ T-cell infiltration and interferon gamma gene expression in the brain which perturbed dopaminergic markers causing significant dopamine depletion. In both sexes, colitis potentiated effects of sub-threshold doses of the dopaminergic neurotoxicant MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and dopaminergic neuropathology. Consistent with a direct role in mediating inflammation-induced death, peripheral CD8+ T-cell depletion prevented colitis-induced reductions in dopaminergic markers.
Conclusions
These novel findings elucidate mechanisms by which gastrointestinal inflammation confers neurological vulnerability to PD in a sex-specific manner and suggest potential new avenues for immunomodulatory therapeutic interventions to delay or prevent progression of PD pathology responsible for motor symptoms.