Cutforth, T. | bioRxiv Science

bioRxiv2022

Mural norrin/β-catenin signaling regulates Lama2 expression to promote neurovascular unit assembly

Neurovascular unit (NVU) assembly and barrier maturation rely on vascular basement membrane (vBM) composition. Laminins, a major vBM component, are critical for these processes, yet which signaling pathway(s) regulate their expression remains unknown. Here we show that mural cells have active Norrin/{beta}-catenin signaling during central nervous system development. Bulk RNA sequencing and validation using P10 and P14 wild-type versus Apcdd1-/- retinas reveal that Lama2 (Laminin-2 chain) mRNA and protein levels are increased in mutant vasculature undergoing higher Norrin/{beta}-catenin signaling. Mural cells are the main source of Lama2, and {beta}-catenin activation induces Lama2 expression in mural cells in vitro. Markers of mature astrocytes including Aquaporin-4 (a water channel in astrocyte endfeet) and Integrin-6 (a laminin receptor) are upregulated in Apcdd1-/- retinas following higher Lama2 vBM deposition. Thus, the Norrin/{beta}-catenin pathway regulates Lama2 expression in mural cells to promote NVU assembly and neurovascular barrier maturation. SUMMARYBiswas et al., demonstrate that Norrin/{beta}-catenin signaling is active in CNS mural cells and regulates Lama2 deposition in the vascular basement membrane, promoting neurovascular unit assembly and blood-CNS barrier maturation.

developmental biology↗

bioRxiv2022

Interaction of an α-synuclein epitope with HLA-DRB1*15:01 initiates early enteric features of Parkinson's disease in humanized mice

Enteric symptoms, including constipation, are hallmarks of prodromal Parkinsons disease (PD) that can appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific -synuclein-(-syn)-derived epitopes. One epitope, -syn32-46, binds with strong affinity to the HLA-DRB1*15:01 allele implicated in autoimmune diseases. We report that -syn32-46 immunization in a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation leading to loss of enteric neurons, damage of enteric dopaminergic neurons, constipation and weight loss. -Syn32-46 immunization activates innate and adaptive immune gene signatures in the gut and induces changes in CD4+ TH1/ TH17 transcriptome that resemble tissue resident memory cells found in mucosal barriers during inflammation. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration. Therefore, interaction of -syn32-46 and HLA-DRB1*15:0 is critical for gut inflammation and CD4+ T cell-mediated loss of enteric neurons in humanized mice, suggesting potential mechanisms of prodromal enteric PD. HIGHLIGHTS AND eTOC BlurbO_LI-syn32-46 immunization of an HLA-DRB1*15:01 mouse triggers weight loss and constipation. C_LIO_LI-syn32-46 immunizations induce gut inflammation, loss of enteric neurons and damage to dopaminergic neurons. C_LIO_LI-syn32-46 immunization induces innate and adaptive immune responses in the gut. C_LIO_LIDepletion of CD4+, but not CD8+, T cells partially rescues enteric neural loss. C_LIO_LIAn interaction between -syn32-46 and HLA-DRB1*15:01 is critical for this model of prodromal PD. C_LI Parkinsons disease (PD) patients exhibit elevated number of circulating T cells that recognize -synuclein-(-syn)- epitopes, particularly during early disease stages. One epitope, -syn32-46, interacts with the HLA-DRB1*15:01; however, its role in PD pathogenesis remains unknown. Garretti et al. show that -syn32-46 immunization of a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation, a loss of enteric neurons, constipation and weight loss, suggesting a critical role for -syn autoimmunity in HLA-DRB1*15:01 carriers in prodromal PD.

neuroscience↗