2025/02/14 by Nisha S. Pulimood, Louise Thiry, Ye Man Tang +1 · 1 voice
Neuroscience · Biochemistry, Genetics and Molecular Biology · #Neuroinflammation and Neurodegeneration Mechanisms #Adenosine and Purinergic Signaling #Inflammasome and immune disorders
paper · pdf · doi:10.1101/2025.02.13.638162
openalex publication_date 2025/02/14 · openalex created_date 2025/02/14 · openalex updated_date 2026/07/15
Abstract 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. Summar y This study describes phenotypic alterations in C9orf72 -ALS/FTD microglia implicating extracellular matrix remodeling and inflammasome activation in microglia-mediated neurodegeneration in ALS/FTD.