# Elucidating the function of Ubiquilin-2 in Synucleinopathies

> **NIH NIH F99** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $38,840

## Abstract

PROJECT SUMMARY/ABSTRACT
Perturbations in protein quality control have been implicated in many age-related neurodegenerative diseases,
which are typically characterized by the accumulation of aggregated proteins such as a-synuclein. Recent
studies have shown that ubiquilin-2 (UBQLN2), a ubiquitin-dependent protein quality control protein, co-localizes
with protein aggregates in major causes of Alzheimer’s disease and related dementias (ADRD), including Lewy
body dementia and Parkinson’s disease, among others. The interaction between UBQLN2 and disease
aggregates implicates UBQLN2 as a potential factor in these disorders. UBQLN2 contains N-terminal ubiquitin-
like (UBL) and C-terminal ubiquitin-associated (UBA) domains that allow UBQLN2 to shuttle ubiquitinated
substrates to the proteasome for degradation. UBQLN2 may also target proteins for degradation by autophagy,
although this is not as well established in the literature. This proposal will build on recent models and reagents
developed in our laboratory to explore the role of UBQLN2 in synucleinopathies. Several studies have shown
that UBQLN2 co-localizes with a-synuclein aggregates in disease, but it is unknown whether UBQLN2 normally
plays a role in handling a-synuclein or the other prominent proteins underlying ADRD. Preliminary studies have
shown that UBQLN2 overexpression markedly reduces
a-synuclein levels, while UBQLN2 knockdown increases
a-synuclein levels. This proposal will define the role of UBQLN2 in clearing
a-synuclein, both normally and in
disease states. To accomplish this goal, I will use mouse models to investigate the role of UBQLN2 in clearing
a-synuclein in vivo and determine if UBQLN2-mediated clearance ameliorates a-synuclein pathology. I will also
use cellular models to investigate the mechanism by which UBQLN2 regulates a-synuclein, making use of
domain deletion mutants to investigate the role of ubiquitin, chaperone, and proteasome binding domains on
UBQLN2 in mediating the clearance of a-synuclein. The proposed studies will lead to a better understanding of
the role of protein quality control pathways in neurodegenerative disease and may reveal novel therapeutic
targets for age-related dementias. This work will also be foundational to my continued graduate and postdoctoral
training as I prepare for a career as an independent scientist.

## Key facts

- **NIH application ID:** 10069445
- **Project number:** 1F99NS118719-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Stephanie Suzette Sandoval-Pistorius
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,840
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069445

## Citation

> US National Institutes of Health, RePORTER application 10069445, Elucidating the function of Ubiquilin-2 in Synucleinopathies (1F99NS118719-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10069445. Licensed CC0.

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