# Pathway discovery for ubiquilin-associated ALS/Dementia

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $421,841

## Abstract

Project summary
The overarching goal of this study is to use complementary Drosophila, and human iPS-induced neurons 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 chaperone factors for proteins that are
destined for degradation by the proteasome. UBQLN1 and UBQLN2 share 74% amino acid identity, with the
most striking difference being a proline-rich-repeat (PRR) domain that is unique to UBQLN2. Missense
mutations within the UBQLN2 PRR cause familial, X-linked, forms of ALS/FTD, whereas 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
ALS/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 neurodegeneration phenotypes—including eye degeneration, motor
defects, and lifespan shortening—that were more severe than phenotypes caused by equivalent expression of
UBQLN2WT. A second chromosome deficiency screen identified 36 genetic intervals that either enhanced or
reduced UBQLN2ALS toxicity and subsequent mapping has implicated endolysosomal transport and axonal
guidance genes as key disease pathways. In this exploratory R21 grant proposal we will leverage the
Drosophila UBQLN2-ALS model to answer the following questions concerning the mechanisms of UBQLN2
toxicity: (i) What genes and pathways contribute to UBQLN2-mediated neurodegeneration? (ii) What are the
impacts of UBQLN2ALS mutants on endolysosomal dynamics? (iii) Can Drosophila genetic screens be
leveraged to understand UBQLN2-mediated neurodegeneration in human iPS derived neurons? The proposed
experiments will identify genetic determinants of UBQLN2-associated neurodegeneration with broader
implications for understanding ALS/dementia and other neurodegenerative diseases involving pathologic
protein accumulation.

## Key facts

- **NIH application ID:** 10129143
- **Project number:** 1R21AG065896-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Sang Hwa Kim
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $421,841
- **Award type:** 1
- **Project period:** 2021-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129143

## Citation

> US National Institutes of Health, RePORTER application 10129143, Pathway discovery for ubiquilin-associated ALS/Dementia (1R21AG065896-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10129143. Licensed CC0.

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