Combining expression with splicing analyses of the astrocyte transcriptome, coupled with translatome and proteome data, we find that IR is prevalent in healthy quiescent hiPSC-derived astrocytes but that ALS astrocytes share a common decreased IR signature, which is a conserved phenomenon across VCP, C9orf72 and SOD1 mutations. Here, SOD1 is linked to amyotrophic lateral sclerosis.