Dysregulated Expression of Inflammasome and Extracellular Matrix Genes in

Hexanucleotide repeat expansion (HRE) in the non-coding region of the gene C9orf72 is the most prevalent mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 HRE contributes to neuron degeneration in ALS/FTD through both cell-autonomous mechanisms and non-cell autonomous disease processes involving glial cells such as microglia. The molecular mechanisms underlying the contribution of C9orf72-HRE microglia to neuron death in ALS/FTD remain to be fully elucidated. In this study, we generated microglia from human C9orf72-HRE and isogenic iPSCs using three different microglia derivation methods. RNA sequencing analysis reveals a cell-autonomous dysregulation of extracellular matrix (ECM) genes and genes involved in pathways underlying inflammasome activation in C9orf72-HRE microglia. In agreement with elevated expression of inflammasome components, conditioned media from C9orf72-HRE microglia enhance the death of C9orf72-HRE motor neurons implicating microglia-secreted molecules in non-cell autonomous mechanisms of C9orf72 HRE pathology. These findings suggest that aberrant activation of inflammasome-mediated mechanisms in C9orf72-HRE microglia results in a pro-inflammatory phenotype that contributes to non-cell autonomous mechanisms of motor neuron degeneration in ALS/FTD.