# Deciphering the role of ER stress in ALS pathogenesis caused by UBQLN2 mutations

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $547,956

## Abstract

Summary
This proposal focuses on UBQLN2, missense mutations in which cause dominant inheritance of amyotrophic
lateral sclerosis with frontotemporal dementia (ALS-FTD). UBQLN proteins facilitate clearance of misfolded
proteins from cells through the autophagy and proteasome degradation pathways, including in ER-associated
degradation (ERAD). Disturbances in ERAD lead to induction of ER stress, chronic induction of which is
implicated in the pathogenesis of neurodegenerative diseases, including ALS. There is growing appreciation
that ER stress may be involved in ALS pathogenesis because targeting of elements that regulate this signaling
response can alleviate disease. However, we not only lack good understanding of the underlying mechanisms
by which mutations in ALS genes trigger ER stress, but also good animal models of the mutations. We recently
generated transgenic mice lines that express either wild type (WT) or the P497S or P506T UBQLN2 mutations
that cause ALS-FTD. The lines expressing the UBQLN2 mutations develop motor neuron disease and
cognitive deficits, recapitulating key features of the human disease. By contrast, the WT lines are devoid of
disease. Examination of protein changes in the spinal cord of early and the end-stage mutant UBQLN2 lines
revealed robust elevation of ER stress and autophagy markers, suggesting protein homeostasis has been
perturbed. ER stress triggers the activation of Ire1α, PERK and ATF6 signaling pathways, collectively called
the unfolded protein response (UPR). There are two phases of UPR: an adaptive phase, where attempts are
made to restore protein homeostasis, which, if unsuccessful, triggers a terminal cell death phase. Studies have
shown that genetic or pharmacological methods that prolong the adaptive phase, or which block the cell death
phase, delay disease in SOD1 mouse models of ALS. In this application we will utilize similar strategies to
directly test whether modulation of UPR signaling, or autophagy, will alleviate disease in our UBQLN2 mouse
models of ALS-FTD. There are six aims. In Aim 1 we will use in vitro cell and biochemical assays to gain
mechanistic insight into how UBQLN2 mutations interfere with ERAD. In Aim 2 we will evaluate if prolongation
of the adaptive phase of ER stress, by genetic deletion of GADD34, alleviates disease symptoms in mice
carrying the P497S UBQLN2 mutation. In Aim 2 we will evaluate if genetic deletion of CHOP, a molecule
involved in execution of cell death, alleviates disease in mutant P497S mice. In Aim 4 we will evaluate whether
genetic deletion of ASK1, a kinase that acts downstream of Ire1α to drive cell death signaling, alleviates
disease in P497S mutant mice. In Aim 5 we will assess if enhancement of autophagy will alleviate any disease
in our UBQLN2 lines. In Aim 6 we will use co-culture experiments to determine if astrocytes from our UBQLN2
mouse models can induce non-cell autonomous death of MN. The results of this research will provide
important insight ...

## Key facts

- **NIH application ID:** 9934290
- **Project number:** 5R01NS100008-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Mervyn J Monteiro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $547,956
- **Award type:** 5
- **Project period:** 2017-09-28 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934290

## Citation

> US National Institutes of Health, RePORTER application 9934290, Deciphering the role of ER stress in ALS pathogenesis caused by UBQLN2 mutations (5R01NS100008-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934290. Licensed CC0.

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