# Protein Homeostasis and Proteotoxicity Mechanisms

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2021 · $53,760

## Abstract

Contact PD/PI: Lin, Jonathan
Protein misfolding arises in many neurodegenerative diseases. The mechanisms by which protein misfolding
causes cell death and disease are poorly understood. The broad, long-term research objectives are: 1) to
decipher the cellular, molecular, and genetic mechanisms that cause neurodegeneration, and 2) to develop
new therapies to prevent and treat neurodegenerative diseases through correction of cellular protein misfolding
in people. The Unfolded Protein Response (UPR) is a conserved intracellular signal transduction mechanism
essential for cellular protein homeostasis. The UPR activates transcriptional programs that induce
chaperones, protein folding enzymes, and protein degradation pathways (proteasome and autophagy). The
UPR also regulates the speed of translation to match the amount of newly synthesized polypeptides to cellular
protein folding capacity. If protein misfolding persists, the UPR triggers apoptosis. The UPR may be a
potential pathomechanism underlying diseases arising from protein misfolding. PERK encodes a
serine/threonine kinase that regulates the UPR. In people, GWAS identified PERK as a genetic risk factor for
the tauopathy neurodegenerative disease, Progressive Supranuclear Palsy (PSP). This research investigates
how PERK causes PSP in these Specific Aims. Aim 1 will investigate PERK's role in mediating
neurodegeneration caused by environmental chemical toxins that increase risk of tauopathy. PERK activity will
be assessed in human stem cell-derived neurons treated with PSP-linked agents. Small molecule proteostasis
agents will be tested for their efficacy in rescuing neuronal damage linked to environment agents. Aim 2 will
analyze the enzymatic properties of PERK heterodimers compared to homodimers. Isogenic stem cell-derived
neurons will be employed. In parallel, recombinant PERK heterodimers will be generated and characterized
using small molecule heterodimerizering compounds. Aim 3 will investigate the molecular and biochemical
basis for selective tau neuropathology in the brain. Postmortem human brain tissues from vulnerable and
resistant brain regions will be compared for UPR activity. Genotyped brain cases will be examined to see how
risk PERK allele expression affects tau neuropathology. PERK is an essential regulator of protein quality in
cells, and human PERK alleles are genetic risk factors for tauopathy neurodegeneration. These studies will
have a positive impact by elucidating fundamental molecular pathomechanisms of PERK signaling in PSP.
These studies may also reduce the clinical burden of PSP and related tauopathy neurodegenerative diseases
by development of novel therapeutic strategies based on pharmacologic regulation of cellular protein quality
homeostasis.
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Project Summary/Abstract

## Key facts

- **NIH application ID:** 10404453
- **Project number:** 3R01NS088485-07S1
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** JONATHAN LIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $53,760
- **Award type:** 3
- **Project period:** 2015-02-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404453

## Citation

> US National Institutes of Health, RePORTER application 10404453, Protein Homeostasis and Proteotoxicity Mechanisms (3R01NS088485-07S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10404453. Licensed CC0.

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