# Endoplasmic Reticulum Stress in Neurodegeneration

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2022 · —

## Abstract

Neurodegenerative diseases are a significant cause of morbidity and mortality in elderly Veterans. No cures
exist for neurodegenerative diseases, because the cellular, molecular, and genetic mechanisms that cause
neurons to die with age are poorly understood. Our long-term objective is to decipher the mechanisms
required for neuronal function and survival and to identify how dysfunction of these mechanisms contribute to
progressive age-associated neurodegenerative diseases. Comprehensive genome wide studies of patients
with late-onset Alzheimer's disease and Progressive Supranuclear Palsy recently identified the eukaryotic
translation initiation factor 2α kinase 3/PKR-like endoplasmic reticulum kinase (EIF2AK3/PERK) gene as a
genetic risk factor for neurodegeneration. EIF2AK3/PERK encodes an endoplasmic reticulum transmembrane
protein kinase that is essential for cells to survive pathologic and environmental conditions that cause
misfolded proteins and endoplasmic reticulum stress. In response to misfolded proteins and ER stress,
EIF2AK3/PERK dimerizes to activate its kinase domain. Multiple EIF2AK3/PERK haplotypes with various
amino acid substitutions are found in the human population. The function of EIF2AK3/PERK in neurons and
the mechanism by which some EIF2AK3/PERK haplotypes cause neurodegeneration are unknown. We
recently discovered that EIF2AK3/PERK haplotypes associated with neurodegeneration have significantly
reduced kinase activity compared to protective haplotypes. We also found that neurons generated from skin
fibroblasts of patients with high-risk EIF2AK3/PERK haplotypes showed impaired EIF2AK3/PERK signaling in
response to ER stress. Last, we found that EIF2AK3/PERK signaling is robustly activated in a mouse model of
tauopathy neurodegeneration. Based on these preliminary findings, our central hypothesis is that
EIF2AK3/PERK is activated during neurodegeneration to preserve neuronal cell function and viability, and loss
of EIF2AK3/PERK function leads to increased protein misfolding and increased ER stress that ultimately cause
neuronal cell death and neurodegeneration. We propose cellular, molecular, and genetic experiments to test
this hypothesis and determine the function of EIF2AK3/PERK in neurodegeneration. First, we will characterize
the biochemical and enzymatic activities of high-risk and low-risk human EIF2AK3/PERK associated with
neurodegeneration. We will perform biochemical studies of recombinant EIF2AK3/PERK proteins to analyze
the functional consequences of amino acid alterations associated with human haplotype variants. Second, we
will test if modulation of EIF2AK3/PERK signaling prevents disease in the PS19 transgenic mouse model of
neurodegeneration. We will cross PS19 mice with genetically modified mice that increase EIF2AK3/PERK
signaling. We will treat PS19 mice with orally available drugs that increase or inhibit EIF2AK3/PERK signaling.
We will perform molecular, histologic, and behavioral studies to examine ho...

## Key facts

- **NIH application ID:** 10316258
- **Project number:** 5I01RX002340-07
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** JONATHAN LIN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-02-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316258

## Citation

> US National Institutes of Health, RePORTER application 10316258, Endoplasmic Reticulum Stress in Neurodegeneration (5I01RX002340-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10316258. Licensed CC0.

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