# Regulation of lysosome positioning and function by the unfolded protein response

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $322,642

## Abstract

Project Summary/Abstract
 The broad goals of this research proposal are to understand how cells mitigate the aggregation
of proteins that underlie neurodegenerative diseases, and how these mechanisms are influenced by
stress pathways and organelle trafficking. There are no cures for Huntington’s, Parkinson’s, and
Alzheimer’s diseases, so exploring new mechanisms for how cells respond to protein aggregation is
important for offering new therapeutic approaches. The first goal of this proposal is to understand how
cells degrade the disease-causing form of the Huntington protein, in particular as it misfolds but before
it forms the large aggregates that are found in the brains of patients. These intermediate, oligomeric
forms of the Huntington protein are thought to be the most toxic, yet we do not know the mechanisms
through which cells most effectively degrade them. Guided by preliminary data, we will explore how
cells employ late endosome-mediated microautophagy in this degradation. Microautophagy is not well-
understood at a mechanistic level, especially in mammalian cells, and this proposal is also designed to
provide more general insights and tools to study this fundamental cellular process. The second overall
goal of this proposal is to understand the relationships between protein aggregation, stress in the
endoplasmic reticulum (ER), and organelle trafficking/positioning. Many neurodegenerative diseases
induce ER stress, yet the complicated interplay between ER stress response pathways and
neurodegeneration is not well-understood enough to provide a clear path for manipulating these stress
pathways therapeutically. This proposal seeks to understand how a particular aspect of the ER stress
response, involving the degradation of a specific mRNA and subsequent repositioning of late
endosomes and lysosomes, affects the degradation and aggregation of the Huntington protein.
Investigating this stress response will also help us to understand how cells maintain homeostasis in the
ER, which is important in many human diseases including cancer and diabetes.

## Key facts

- **NIH application ID:** 10202203
- **Project number:** 2R35GM119540-06
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** JULIE HOLLIEN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $322,642
- **Award type:** 2
- **Project period:** 2016-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202203

## Citation

> US National Institutes of Health, RePORTER application 10202203, Regulation of lysosome positioning and function by the unfolded protein response (2R35GM119540-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10202203. Licensed CC0.

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