Enhancement of the integrated stress response (ISR), an innate cellular protective signalling pathway, might be useful in the treatment of multiple sclerosis, according to a new study published in Brain. Chen et al. showed that Sephin1, which inhibits the dephosphorylation of the ISR target eIF2α, prolonged eIF2α phosphorylation in stressed primary oligodendrocytes, thereby prolonging the protective response. The researchers showed that Sephin1 delayed the onset of clinical symptoms in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, and that Sephin1 in combination with interferon-β provided additional benefits in slowing disease progression. Consistent with the idea that Sephin1 inhibits PPP1R15A (a subunit of the protein complex that dephosphorylates eIF2α), mice with mutant PPP1R15A showed delayed onset of EAE similar to the Sephin1-treated mice.