Alleviating Mitochondrial Dysfunction in PERK-deficient Neurodegenerative Disease

PROJECT SUMMARY
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are hallmarks of pathologic aging and are
intricately linked in the onset and pathogenesis of etiologically-diverse neurodegenerative disorders including
Alzheimer’s disease (AD) and related dementias (ADRDs). This has led to significant interest in understanding
how cells regulate mitochondria in response to ER stress. Intriguingly, the ER stress-responsive kinase PERK
is localized to ER-mitochondria contact sites where it acts as an effector of both the unfolded protein response
(UPR) and the integrated stress response (ISR). Additionally, PERK-dependent transcriptional and translational
signaling modulates nearly all aspects of mitochondrial biology including remodeling of mitochondrial cristae and
respiratory complexes to enhance energy capacity, regulation of mitochondrial proteostasis (i.e., protein import,
chaperone activity, and proteolysis), and remodeling of membrane phospholipid composition to induce protective
mitochondrial elongation. Through these mechanisms PERK protects mitochondria during ER stress; however,
persistent PERK activation induced by severe or chronic ER stress leads to apoptosis. Thus, PERK signaling
both promotes adaptive mitochondrial remodeling and dictates cell fate in response to varying levels of cellular
stress. The importance of PERK in regulating adaptation and survival is further supported by clinical, genetic,
and pharmacologic evidence demonstrating that imbalanced PERK signaling contributes to the pathogenesis of
etiologically-diverse neurodegenerative diseases. Hypomorphic variants in the gene that encodes PERK
(EIF2AK3) predispose individuals to tauopathies such as progressive supranuclear palsy (PSP) and late-stage
AD. In addition, exogenous PERK activation mitigates tau pathology in PSP, further indicating that protective
PERK signaling is insufficient in the pathogenesis of this disease. Collectively, these observations establish
PERK as a critical regulator of mitochondrial adaptation to cellular insult and suggest that imbalances in PERK
signaling contribute to mitochondrial dysfunction implicated in neurodegenerative disease pathogenesis. Using
cell culture models derived from patients expressing a hypomorphic PERK variant, I will show that deficiencies
in PERK signaling impair mitochondria and contribute to neurodegenerative phenotypes such as tau pathology
(Aim 1). Further, I will demonstrate that pharmacologic activation of the ISR—a stress-responsive program
comprised of the eIF2α kinases GCN2, HRI, PKR, and PERK—mitigates mitochondrial dysfunction and improves
neuronal survival in a human neuronal model of PERK-deficient neurodegeneration (Aim 2). These efforts are
significant as they will define a critical role for PERK in regulating mitochondrial adaptation during
neurodegeneration and establish pharmacologic ISR activation as a potential therapeutic strategy against
neurodegenerative disease—for which no disease-modifying treatments are currently available.

Grant Number: 7F30AG081061-03
NIH Institute/Center: NIH
Principal Investigator: Kelsey Baron