MYC-Driven Gliosis Impairs Neuron-Glia Communication in Amyotrophic Lateral Sclerosis
Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice, and patient-derived cells modeling TDP-43, SOD1, and C9orf72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioral abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocytic EVs that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS. Overall design: RNA-seq was performed on purified astrocytes (ACSA+), purified oligodendrocytes (O4+) isolated from cortices and spinal cords of TDP-43Q331K mice. Purified microglia (Cd11b+) was obtained from the same mouse model but from cortices only. Samples were collected from mice at either 3, 6, or 10 months. Moreover, samples from omomyc treated astrocytes are included.