Enteric glia, neuropeptides, and Parkinson’s: impacts of calcitonin gene-related peptide on gut alpha synuclein

Parkinson's disease is a neurodegenerative disorder pathologically characterized by accumulation of misfolded α-synuclein in the central and peripheral nervous systems, influencing symptomology at both sites. Calcitonin gene-related peptide (CGRP), a neuropeptide produced in the brain and intestine, has been linked with altered α-synuclein aggregation. This study examines the role of calcitonin gene-related peptide in modulating enteric α-synuclein accumulation and enteric glial cell reactivity using an ex vivo slice culture model from A53T^+/- human α-synuclein mutant mice. In slices treated with calcitonin gene-related peptide, α-synuclein immunoreactivity was elevated in myenteric neurons within 24 h. A stark elevation in gut mucosal calcitonin gene-related peptide immunoreactivity was revealed to be predominantly S100β+ enteric glia cells rather than neuronal fibers, pointing toward a reactive enteric glial cell phenotype. In addition, CGRP treatment increased enteric glial cell count in the mucosa in wildtype colon slices without evidence of incorporation of the DNA synthesis marker 5-ethynyl-2'-deoxyuridine indicating a lack of cell proliferation. Mucosal increases in enteric glial cell counts were accompanied by a decrease in these cells in the submucosa. This supports the idea that an inflamed gut environment may shift enteric glial cells to a reactive phenotype, inducing alterations in their number and anatomic localization. These data implicate calcitonin gene-related peptide in the accumulation of enteric α-synuclein, an effect potentially driven by an inflammatory environment that we hypothesize is due in part to enteric glial cell activation.<b>NEW & NOTEWORTHY</b> Gastrointestinal symptoms of Parkinson's disease (PD) are an emerging area of investigation with implications for disease etiology. Utilizing intestinal ex vivo slices from a PD mouse model, Templeton et al., identify calcitonin gene-related peptide (CGRP) as a key modulator of enteric α-synuclein accumulation and enteric glial reactivity. These findings suggest that targeting peripheral CGRP signaling pathways in the enteric nervous system may represent a novel therapeutic approach for early intervention in PD.