Multi-omics characterization of immune triggers in Moyamoya disease

Introduction

This project aims to characterize a recently discovered link between a rare genetic disorder of the brain, called Moyamoya disease (MMD), and the cellular immune response against microbial infections. MMD is characterized by a progressive occlusion of arteries at the base of the brain leading to stroke. Mutations in Ring Finger Protein 213 (RNF213) represent the most common genetic cause of MMD; however, it is suggested that environmental stimuli are needed to trigger disease onset in genetic carriers.

Discovery of RNF213

Intriguingly, we recently discovered RNF213 as a novel antibacterial protein that can target intracellular Listeria (Gram+), providing strong protection to Listeria both in vitro and in vivo.

Interaction with Other Pathogens

Similarly, RNF213 can bind intracellular Salmonella (Gram-), mediating its ubiquitin-dependent degradation. Moreover, we also identified RNF213 as a cellular sensor for proteins modified by ISG15 (ISGylated proteins), a ubiquitin-like modification of the immune system induced by interferon.

Implications of Findings

These observations not only uncover RNF213 as a novel key antimicrobial protein, but they also suggest an important role for the immune system in triggering MMD.

Hypothesis

MULTIMOYA starts from the hypothesis that dysregulated immune responses to infections might trigger MMD disease onset in patients carrying mutations in RNF213.

Research Approach

To investigate this hypothesis, we will:

1. Determine whether MMD patient-derived immune cells respond differently to:

   • Interferon
   • LPS
   • Bacterial infection

2. Map altered pathways using a multi-omics approach, combining:

   • Genomics
   • Transcriptomics
   • Proteomics
   • (Tracer) metabolomics data

Validation of Results

Results will be validated by biochemical and imaging analysis in relevant patient-derived/like cellular models as well as in mouse models of MMD that we will establish.

Conclusion

Together, these experiments will provide unprecedented insight into MMD-related immune responses and fundamental processes that link cellular immunity with vascular disease.