Grant: Project Grant

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease causing the death of motoneurons (MN), the cellular population controlling muscles. Despite colossal efforts to understand ALS, its causes are still unclear, making most treatments ineffective. A better understanding of the disease is thus imperative to generate targeted therapies. In ALS, motoneurons and inflammatory cells, communicate by releasing factors that contribute to the pathology, one of them is PPIA, which is highly secreted by astrocytes. Our data showed the presence of EMMPRIN, PPIA main receptor, on MN and astrocytes in ALS conditions, suggesting the specific activation of the PPIA/EMMPRIN pathway in these cells. PPIA is known to have proinflammatory properties, and activation of EMMPRIN induces matrix metalloproteinases (MMPs) release, necessary for extracellular matrix remodeling. Interestingly, we showed that an anti-EMMPRIN antibody reduces astrocytes activation, MMPs and pro-inflammatory factors release. We thus hypothesize that the astrocytic PPIA/EMMPRIN interaction has a pathological role in the complex cellular communication of ALS and suggest it as a therapeutic target for the disease. This project aims to understand the astrocytic activation of the PPIA/EMMPRIN pathway in the ALS cellular communication and how this interaction is responsible for neurodegeneration and neuroinflammation. This study is a collaborative effort in which primary cells, mouse models and iPSC from ALS patients will be used to investigate our hypotheses. A multimodal approach, that includes imaging, molecular biology, gene expression analysis and manipulation, as well as behavioural assessments, will be used to reveal how the complex network of cells interact to induce the disease. Overall, we hope to unravel a new molecular mechanism behind cellular communication, neuronal death and neuroinflammation in ALS, and to provide evidence for a potential new target for the treatment of the disease.