These PLP/Fv2E-PERK mice express a mutant form of Eif2ak3 under direction of the Plp1 promoter in oligodendrocytes. PERK is an endoplasmic reticulum (ER) transmembrane protein, which is induced by ER stress caused by malfolded proteins. Phosphorylation of the alpha subunit of Eif2ak leads to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This protein is thought to modulate mitochondrial function. Mutations in this gene are associated with Wolcott-Rallison syndrome and early onset diabetes.

The PERK protein contains three functional domains: a stress-sensing ER luminal domain, an ER transmembrane domain, and a cytosolic eIF2 kinase domain. Activation of PERK signaling is initiated by PERK dimerization and autophosphorylation, which is driven by the stress-sensing ER lumenal domain of PERK. This PLP/Fv2E-PERK strain contains an Fv2E-PERK, an artificial PERK derivative, which was generated by fusing the eIF2 kinase effector domain to a polypeptide containing two modified FK506 binding domains. These modified domains allow temporally controlled activation of PERK signaling, in the absence of ER stress, specifically in oligodendrocytes, by the administration of AP20187, a synthetic compound that induces homodimerization of fusion proteins containing the modified FK506 binding domains.

Expression is evident in the central nervous system of the transgenic mice, but not in other organs studied, such as heart, lung, liver, kidney, or spleen. To activate the transgene in oligodendrocytes, mice are given intraperitoneal injections of AP20187 daily. This expression significantly attenuates experimental autoimmune encephalomyelitis (EAE) severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. EAE is an experimental model of multiple sclerosis.

Hemizygous PLP/Fv2E-PERK mice are viable and fertile.

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These PLP/Fv2E-PERK mice express a mutant form of Eif2ak3 under direction of the Plp1 promoter in oligodendrocytes. Eif2ak3 in these mice contains two modified FK506 binding domains, activity of which can be controlled by a FK506 dimerizing agent, AP20187. Activation of Eif2ak3 by AP20187 significantly attenuates experimental autoimmune encephalomyelitis (EAE) severity, which is associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration.

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