# Integrating Quality Control: Studies of UBQLN2 in Age-Related Neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $156,000

## Abstract

Abstract
Mutations in Ubiquilin2 (UBQLN2) were recently identified as a cause of Frontotemporal Dementia and
Amyotrophic Lateral Sclerosis (FTD/ALS) associated with TDP43 deposition, and UBQLN2 itself has emerged
as a sensitive marker of pathology in a substantial portion of sporadic and familial FTD/ALS. UBQLN2 is also
one of four closely related ubiquilins, a family of ubiquitin adaptor proteins implicated in ubiquitin-dependent
protein quality control in the nervous system. Although mounting evidence implicates UBQLN2 and other
ubiquilins in numerous age-related neurodegenerative diseases defined by protein accumulation, their
functions in brain health and disease remain poorly understood. Moreover, the mechanisms by which
mutations in UBQLN2 cause FTD/ALS are unknown. The current proposal investigates these critical gaps in
knowledge. Our primary goals are to define pathogenic mechanisms in UBQLN2-mediated FTD/ALS and to
gain insight into the cellular pathways driving TDP43 deposition and neurodegeneration in FTD/ALS. In three
specific aims employing complementary approaches (biochemistry, animal models, and automated
microscopy), our investigative team will seek to 1) define the molecular properties driving aggregation of
mutant UBQLN2, 2) explore the functional consequences of UBQLN2 aggregation in mouse models, and 3)
investigate how mutant UBQLN2 alters TDP43 homeostasis in neurons. The proposed studies build on: novel
biochemical insights into the distinct properties of wild type and mutant UBQLN2; newly generated mouse
models expressing wild type or mutant UBQLN2 that show robust aggregate pathology selectively in mutant
UBQLN2 mice; a completed proteomics screen demonstrating that wild-type UBQLN2 interacts with the two
other brain-expressed ubiquilins, UBQLN1 and UBQLN4; and evidence that TDP43-positive cytoplasmic
puncta accumulate in neurons of mutant UBQLN2 mice, offering a pathway to explore functional links between
UBQLN2 and TDP43. The proposed multi-system approach greatly increases the probability of uncovering
disease mechanisms in FTD/ALS and achieving our long-term objective of finding routes to therapy for this
spectrum of fatal, age-related neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10200456
- **Project number:** 3R01NS096785-10S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Magdalena I Ivanova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,000
- **Award type:** 3
- **Project period:** 2020-09-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200456

## Citation

> US National Institutes of Health, RePORTER application 10200456, Integrating Quality Control: Studies of UBQLN2 in Age-Related Neurodegeneration (3R01NS096785-10S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10200456. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*