# PERK determines polarized targeting of growth factors in neurons

> **NIH NIH R21** · DREXEL UNIVERSITY · 2020 · $441,853

## Abstract

Abstract
The ER stress sensor PERK usually serves to attenuate protein synthesis and activate apoptotic pathways.
Thus, most of the work linking PERK to Alzheimer's disease and to tauophathies focuses on manipulating this
activity. However, the genetic variants of PERK associated with increased risk for neurodegeneration have
recently been shown to have reduced kinase activity, suggesting that the PERK pathway also has important
adaptive functions that may be neuro-protective. Manipulating these protective functions is equally important
for neurodegeneration. We discovered one such function of PERK, which underlies the proper localization of
growth factors to axons and dendrites, which in turn is a pre-requisite for their local secretion and
neuroprotection. PERK is involved in growth factor localization because its deletion in either mouse cortical
neurons or in worm chemosensory neurons abolishes the correct axonal/dendritic distribution and inhibits the
secretion of IGFs and TGFβ. This proposal explores how PERK controls axonal/dendritic localization
and secretion of these neuroprotective growth factors.
In Aim 1 we will determine if the kinase activity of PERK is necessary for growth factor localization in neurons,
whether its main phosphorylation substrate, eIF2α, mediates this activity, and whether the PERK risk alleles
associated with neurodegeneration alter the distribution of growth factors. In Aim 2 we will follow on genetic
data indicating that PERK regulation of growth factor localization depends on components of the calcium
homeostasis machinery, both membrane channels and cytosolic mediators. In both Aims we will combine
genetic analyses of sensory neurons in worms and mice with biochemical analyses, because of the
complementary insights provided by these approaches.
This project will identify a novel cellular pathway that underlies the polarized secretion of growth factor by
neurons and thus their functional connectivity. Understanding how PERK performs this novel protective
function in neurons will open options of manipulating these pathways in presymptomatic AD and tauopathy
models, and into delineating sensitizing vs protective mechanisms.

## Key facts

- **NIH application ID:** 9895969
- **Project number:** 1R21AG063029-01A1
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** TALI GIDALEVITZ
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,853
- **Award type:** 1
- **Project period:** 2020-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895969

## Citation

> US National Institutes of Health, RePORTER application 9895969, PERK determines polarized targeting of growth factors in neurons (1R21AG063029-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9895969. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*