Multiple cell and tissue types factor into neurodegeneration in FTLD-GRN. Data from Marsan et al. (10) indicate that GRN deficiency induces downstream changes in all four cell types of the brain. Atrophy, gliosis, neuronal loss, and TDP-43 poteinopathy are prominent in gray matter, evident at both the subcellular and transcriptional levels. Microglia increase synaptic pruning and display a disease-specific transcriptional profile, including the upregulation of C1q. Astrocytes fail to maintain synapses, resulting in disrupted synapse number and morphology. The downregulation of synaptic genes in neurons include TDP-43 target RNAs associated with TDP-43 nuclear exclusion and cytoplasmic deposition. Although TDP-43 proteinopathy is mild and variable in white matter, other pathological changes, including gliosis, myelin loss, and myelin debris within microglia, are more common. DEGs are highly enriched in oligodendroglia, suggesting that these cells are substantially impacted in FTLD-GRN.