Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease. Although mostly sporadic, major geneticcauses are nucleotide expansions in C9ORF72 and mutations in SOD1, TARDBP and FUS. We have shown that motor neuron deathis non-cell autonomous and that reducing mutant SOD1 in CNS microglia/peripheral macrophages slows disease progression. This suggests that in ALS, mutant gene expression in microglia/macrophages as well as the natural activation response of these cellsbecome deleterious. As ALS is mainly sporadic, thus diagnosed with symptoms already present, acting on disease progression bymodulating microglia/macrophages could benefit all ALS cases.
Our first aim is to find how microglia/ macrophages participate to the disease. Importantly, the specific disease contribution ofperipheral macrophages, easier to reach than CNS microglia to reduce motor neuron loss, is unknown. In addition, targeting peripheral macrophages would be especially relevant and original to ALS as the biggest part of spinal motor neurons, the axon, liesoutside the CNS. We therefore ask how peripheral macrophages compared to CNS microglia are implicated in ALS and define theirdisease modifying capacity. Approaches include analyzing pathways activated during disease in peripheral nerve macrophages andblood monocyte/macrophages of ALS mice and patients and assessing toxicity of macrophages carrying different ALS mutations towards motor neurons using iPSc and mouse models.
Our second aim is to assess the crucial question whether different ALS genes lead to motor neuron death and deleteriousmicroglia/macrophage responses by gain or loss of function mechanisms. A major focus will be on newly discovered and theremaining unknown ALS genes with approaches including novel mouse modeling and gene discovery.Our project relies on the combined capacities of 4 PIs and 2 supporting clinicians forming this ALS team. The combined expertiseranges from cellular and molecular studies in animal models to use of human derived iPSc cell culture modeling and human geneticsas well as human postmortem tissue analysis. Results will contribute to basic understanding