“…In addition to PERK, other kinases including double-stranded RNA-activated protein kinase (PKR), general control non-derepressible-2 kinase (GCN2), and heme-regulated inhibitor kinase (HRI), can phosphorylate eIF2α and together make up the integrated stress response (ISR). Enhanced PKR activation has been observed in patients and mouse models of AD, PD, and HD [38,39,40,41,42,43,44,45], and the inhibition of PERK, PKR, and GCN2 via genetic and pharmacologic means have shown beneficial effects [46,47,48,49]. Thus, despite eIF2α and the ISR being a protective mechanism that temporarily halts protein translation in order to alleviate further stress caused by protein misfolding and aggregation, chronic eIF2α-mediated shutdown of global protein synthesis may have substantial negative impact on various neuronal functions that require de novo protein production.…”