However, both ATF6 and PERK branches of the UPR<sup>ER</sup> participate in amelioration of tauopathy by constitutively active XBP-1, possibly through endoplasmic reticulum-associated protein degradation (ERAD).
This review provides an overview of recent progress in animal model studies, which demonstrate that dysregulated PERK accounts for memory deficits and neurodegeneration not only as a detrimental mediator downstream of β-amyloidosis and tauopathy but also as an important determinant upstream of both pathogenic mechanisms in AD.
In contrast, the PERK tauopathy risk variants were distinct from the Wolcott-Rallison variants and introduced missense alterations throughout the PERK protein.
Chronic overactivation of the UPR, particularly the PERK branch, is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the tauopathies.
PERK and eIF2α activation are increasingly recognised in postmortem analyses of patients with neurodegenerative disorders, including Alzheimer's disease, the tauopathies and prion disorders.