# Genetic analysis of UBQLN2-associated neurodegeneration in frontotemporal dementia

> **NIH NIH RF1** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $1,700,040

## Abstract

Project summary
The overarching goal of this study is to use complementary Drosophila and inducible pluripotent stem cells
(iPSC)-derived neuronal models to understand how mutations in the Ubiquilin 2 (UBQLN2) gene cause
amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). UBQLN2 and closely related UBQLN1
belong to a family of eukaryotic ubiquitin (Ub)-binding proteins that function, in part, as chaperones for proteins
that are destined for proteasomal degradation. Missense mutations within a unique, functionally orphan
proline-repeat region (PRR) of UBQLN2 cause X-linked, forms of ALS/FTD, with some patients exhibiting a
pure dementia onset. In addition, ubiquilin histopathology, comprised of dense aggregates of UBQLN2 and
UBQLN1 are observed in most instances of ALS/FTD regardless of UBQLN2 mutation status. To address
pathomechanisms of UBQLN2-associated FTD we exploited the upstream activating sequence (UAS)/GAL4
system to generate isogenic Drosophila strains expressing wild-type (WT) and ALS mutant forms of UBQLN2
in different tissues and cell types. We found that UBQLN2ALS mutants elicited dose-dependent phenotypes—
including eye degeneration, motor defects, and lifespan shortening—that were more severe than phenotypes
caused by equivalent expression of UBQLN2WT. UBQLN2ALSmutants, but not UBQLN2WT, formed
intraneuronal aggregates characteristic of ubiquilin inclusions found in ALS/FTD patients. Unbiased genetic
screens identified more than 30 genetic intervals that either reduced or enhanced UBQLN2ALS mutant toxicity.
Gene mapping studies suggest that endolysosomal pathways are centrally involved in UBQLN2ALS-mediated
neurodegeneration and point toward axon guidance genes and neuronal dependence receptors as potentially
novel disease modifiers. In this R01 grant proposal we will continue genetic studies of UBQLN2-mediated
neurodegeneration in Drosophila, focusing on endolysosomal trafficking and axon guidance as lead pathways
for discovery efforts. Modifier pathways identified in Drosophila will, in turn, inform studies of iPSC-derived
motor neurons (iMNs) expressing endogenous UBQLN2ALS alleles. The specific objectives of Aim 1 are to: (a)
investigate the Rab5 gene and endolysosomal defects in UBQLN2ALS flies; (b) investigate the contributions of
the Unc-5 axon guidance pathway to UBQLN2-mediated neurodegeneration; and (c) map and validate of
UBQLN2ALS modifier genes in Drosophila. The specific objectives of Aim 2 are to: (a) establish functional
defects in UBQLN2ALS iMNs; (b) carry out proteomic analysis of UBQLN2ALS iMNs; and (c) evaluate genes
emerging from Drosophila screens in Aim 1 as genetic modifiers of UBQLN2ALS toxicity in iMNs. The combined
genetic, cellular, and biochemical studies using Drosophila and mammalian iMN models will provide important
new insights into UBQLN2-associated neurodegeneration in ALS/FTD. In addition, pathways identified in our
study are likely to overlap with and inform toxicity pathways insti...

## Key facts

- **NIH application ID:** 10157746
- **Project number:** 1RF1AG069483-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Randal Scot Tibbetts
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,700,040
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10157746

## Citation

> US National Institutes of Health, RePORTER application 10157746, Genetic analysis of UBQLN2-associated neurodegeneration in frontotemporal dementia (1RF1AG069483-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10157746. Licensed CC0.

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