Investigating the role of C9ORF72 and ARLs during Immune Dysregulation and Neurodegenerative Pathology – IMPACTSensors

This proposal investigates the role of the C9orf72 protein in pathological immune responses, focusing on nucleic acid (NA) sensing and inflammation. Vesicular trafficking is a key process for moving molecules between cellular compartments, crucial to recognize and isolate danger signals from pathogens or cellular stress. Disruptions in this system can lead to improper responses, contributing to cancer, autoimmunity and neurodegenerative disorders. Of interest we found that the C9orf72 gene, which carries mutations in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), controls inflammatory responses through the Toll-like receptors, which recognize circulating DNA and RNA. These receptors, regulated by vesicular trafficking, are crucial for immune signaling. Dysregulation of these pathways can lead to autoimmunity by mistakenly targeting self-nucleic acids, resulting in excessive type-I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs). Similarly, trafficking of the cGAS-STING pathway plays a key role in DNA virus detection. In this proposal, we aim to elucidate how C9orf72 regulates the trafficking of TLR7, TLR9 and STING, controlling their activation to prevent inappropriate inflammation. Indeed, our data show that C9orf72 knockout mice develop severe inflammation, with enhanced IFN-I signaling and pDC activation. Moreover, we found that C9orf72 deficiency impacts TLR9 trafficking, and that C9orf72 interacts with ARL11 and ARL14, two small GTPases regulating vesicle traffic, but of unknown roles in the immune system. These findings are highly novel and relevant to decipher the role of C9orf72 in diseases. Thus, our proposed collaboration among 3 complementary and expert teams will provide a comprehensive understanding of these mechanisms and how C9orf72, ARL11 and ARL14 regulate immune responses in vitro and at the animal level; potentially leading to new therapeutic approaches for inflammatory and neurodegenerative diseases.
By investigating the molecular mechanisms of STING trafficking, its evolutively highlt conserved impact in pathological conditions, its multidisciplinary nature of the project and translational potential make it well-suited for consideration within the relevant neuroscience and immune signaling research axes.
This project is fully aligned with the scientific priorities outlined by the commission, as it investigates molecular and cellular assembly, inter-organ interactions, and pathological mechanisms through a multidisciplinary lens. Additionally, the unique training of the supervisor, in top-tier neuroscience and immunology laboratories (Yale University, Nobel laureate mentors) makes her exceptionally qualified to lead this cross-disciplinary research. This combination of scientific innovation, methodological rigor, and supervisory excellence ensures that the project is positioned to generate high-impact findings in both fundamental biology and clinical applications.