PERK signalling in neurodegenerative diseases: From ER stress to mitochondrial dysfunction and therapeutic opportunities

Abstract

The PERK (PKR-like endoplasmic reticulum kinase) pathway is a key branch of the unfolded protein response (UPR), and is crucial for maintaining cellular homeostasis. In neurodegenerative diseases, factors such as misfolded protein accumulation and oxidative stress lead to sustained endoplasmic reticulum stress, thereby causing excessive activation of the PERK pathway. This abnormal activation not only inhibits protein synthesis and promotes apoptosis but also disrupts critical functional connections, such as endoplasmic reticulum-mitochondria contact sites (MAMs). This disruption leads to mitochondrial dysfunction and forms a vicious cycle that drives neuronal death. This article systematically reviews the activation mechanisms of the PERK pathway in diseases such as Alzheimer’s disease and Parkinson’s disease, focusing on its role as a molecular bridge that converts endoplasmic reticulum stress into mitochondrial dysfunction. It also summarizes the latest therapeutic strategies and research progress targeting this pathway, with the aim of providing new insights for the development of neuroprotective therapies.