Recent studies have shown that HRI and GCN2 can act as sensors for mitochondrial stress (Fessler et al, 2020; Guo et al, 2020; Mick et al, 2020); however, the majority of ISR activation seen in models of neurodegenerative disease is dependent on PERK (Smith & Mallucci, 2016). Here, EIF2AK3 is linked to neurodegenerative disease.