The present project aims to investigate the exciting hypothesis that a rare cerebrovascular disease might originate from an aberrant immune response to infection in genetically predisposed individuals. The disease in scope is called Moyamoya, a Japanese name pointing to the fact that incidence is highest in East Asia. The latter results from the fact that predisposing mutations in RNF213 are widespread in the Asian population. Our discovery of RNF213 as a key antimicrobial protein and its function as a binding platform for proteins modified by ISG15 sheds new light on the potential involvement of infection diseases and associated immune responses in the development of Moyamoya. While the main goal is to investigate the above hypothesis from a fundamental point of view, our results could still impact the life of millions of people carrying the p.R4810K RNF213 susceptibility variant in East Asia (including ~2% of the Japanese population). If certain (childhood) infections indeed trigger Moyamoya disease onset in these patients, prophylactic vaccination, therapy or reduced exposure to the culprit pathogen(s) could be considered. In addition, a better understanding of the molecular events driving the pathogenic proliferation of vascular smooth muscle cells in occlusive lesions could lead to novel diagnostic tests or therapies for Moyamoya disease. The potential plasma biomarker already identified in the project exemplifies this, but needs further validation in larger patient cohorts. To gain molecular insight into Moyamoya disease mechanisms, an animal model would be a tremendous breakthrough, along with knowledge on dysregulated pathways mapped by (spatial) omics characterization of patient samples, two focus areas of MULTIMOYA. In this way, the project will gain fundamental insight into processes that link cellular immunity with vascular remodeling, knowledge that is also highly relevant beyond Moyamoya disease.
