# Mechanistic studies and therapeutics for ALS-FTD linked to UBQLN2 mutations

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $504,381

## Abstract

Summary
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder associated with loss
of upper and lower motor neurons. Some ALS patients also develop frontotemporal dementia (FTD). Genetic
findings have linked mutations in different genes to the range of symptoms seen in ALS. This proposal focuses
on UBQLN2, missense mutations in which cause dominant inheritance of ALS-FTD. UBQLN2 is one of four
ubiquilin (UBQLN) proteins found in humans. UBQLN proteins function to clear misfolded proteins from cells
through the proteasome and autophagy pathways. This function could be important in neurodegenerative
diseases, where a build up of misfolded proteins is frequently seen. Therefore, understanding how UBQLN
proteins function and dysfunction has broad implications for neurodegenerative diseases. Animal models of the
disease are useful for understanding the mechanisms of pathogenesis and for therapeutic studies. Toward
such a goal, we generated and characterized transgenic mice carrying Thy1.2 promoter-driven expression of
human UBQLN2 proteins encoding either the wild type (WT) or the P497S or P506S mutants that cause ALS-
FTD. Mouse lines carrying each of the mutations were found to develop motor neuron disease and cognitive
deficits, mimicking the human disease, whereas the WT mice were devoid of motor neuron disease.
Immunoblots of spinal cord proteins revealed a dramatic reduction in TBK1 levels in animals with end-stage
disease in both the mutant UBQLN2 mouse lines compared to non-transgenic animals. The reduction could be
significant because haploinsufficiency of TBK1 expression caused by TBK1 mutations were recently linked to
ALS-FTD. Prompted by these relationships, we examined whether TBK1 binds with UBQLN2. Double
immunofluorescence staining indicated TBK1 and UBQLN colocalize in cells in autophagosomes. Furthermore,
by both immunoprecipitation and GST-pulldown assays we found WT UBQLN2 binds TBK1, but the ALS
UBQLN2 mutant proteins bind more TBK1. We hypothesize that the increased binding with UBQLN2 mutants
alters one or both of the protein's functions. Accordingly, we propose experiments in Aim 1 to study the
functional significance of the interaction, and how mutations in UBQLN2 affect this interaction especially with
regard to the function of the proteins in autophagy, which we found is disturbed in our mutant UBQLN2 mouse
lines. In Aim 2, we will determine whether transgenic overexpression of TBK1, in an effort to restore its levels
in our UBQLN2 mice, will extend survival and delay ALS-FTD symptoms. In Aim 3, will investigate the exciting
possibility, supported by our preliminary studies in double transgenic mice, that overexpression of UBQLN1 in
our mtUBQLN2 lines will delay ALS-FTD symptoms. The outcome of this work is likely to be important both in
terms of its implications for our understanding of the underlying mechanisms involved in ALS-FTD
pathogenesis and because it could reveal whether modulati...

## Key facts

- **NIH application ID:** 9830089
- **Project number:** 5R01NS098243-04
- **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:** $504,381
- **Award type:** 5
- **Project period:** 2017-01-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830089

## Citation

> US National Institutes of Health, RePORTER application 9830089, Mechanistic studies and therapeutics for ALS-FTD linked to UBQLN2 mutations (5R01NS098243-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9830089. Licensed CC0.

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