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

> **NIH NIH RF1** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $2,200,770

## Abstract

Summary
UBQLN2 mutations cause X-linked dominant inheritance of amyotrophic lateral sclerosis with frontotemporal
dementia (ALS/FTD). The encoded ubiquilin-2 protein (UBQLN2) belongs to a small family of conserved
proteins that function to maintain proteostasis by binding and disposing ubiquitinated proteins through the
proteasome and autophagy-lysosomal degradation systems. There is increasing evidence that disruption in
proteostasis by interference in either of these clearing systems cause neurodegeneration. Therefore,
understanding how UBQLN2 proteins function and dysfunction has broad implications for neurodegenerative
diseases. The mechanisms by which UBQLN2 mutations cause pathogenesis are emerging. Towards this
goal, we generated transgenic (Tg) mouse models for the P497S and P506T UBQLN2 mutations, showing that
both mutant lines recapitulate central features of the human disease, including deposition of UBQLN2
inclusions, cognitive deficits, motor neuron disease and TDP-43 pathology. Through proteomic and
immunoblot analysis we found that P497S mutant mice have major alterations in proteins involved in
autophagy and in proteins required for mitochondrial health. Using a novel reporter system in combination with
UBQLN2 knockout (KO) cells, we found ALS/FTD-linked mutations in UBQLN2 impede autophagy by blocking
autophagosome acidification. We tied the defect to a novel function of UBQLN2 in regulation of the
vacuolar(H+)-ATPase pump. Respiration assays of mitochondria purified from the spinal cord revealed mutant
UBQLN2 animals have an age-dependent decline in oxidative phosphorylation. Similar defects were found in
UBQLN2 KO cells, suggesting the functional decline in mitochondrial activity may stem from loss of UBQLN2
function. In support of this idea, we found that wild type (WT) UBQLN2 rescued the mitochondrial function
deficits whereas UBQLN2 bearing an ALS/FTD mutation did not. Furthermore, we found WT UBQLN2 is
required and regulates mitochondrial protein import whereas ALS/FTD mutant UBQLN2 proteins are deficient
of the activity. For this renewal, we propose 4 aims that will capitalize on these exciting discoveries, as well as
other important findings made during the last funding period. In Aim 1 we will determine the molecular
mechanisms by which UBQLN2 functions in vacuolar-ATPase regulation and clarify why ALS/FTD UBQLN2
mutant proteins are disrupted in the activity. In Aim 2 we will determine the molecular mechanisms underlying
UBQLN2 function and dysfunction in mitochondrial protein import and activity. Aim 3 is to test whether
overexpression of UBQLN1 alleviates disease in SOD1 mouse models of ALS. Aim 4 is to recover the two
mutant UBQLN2 mouse lines from sperm cryo-stocks for better phenotypes. The results of this research are
likely to considerably advance our knowledge of the mechanisms by which UBQLN2 proteins function in health
and disease, the lessons of which could be exploited for therapeutic intervention in not only...

## Key facts

- **NIH application ID:** 10373433
- **Project number:** 2RF1NS098243-06
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Mervyn J Monteiro
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,200,770
- **Award type:** 2
- **Project period:** 2017-01-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373433

## Citation

> US National Institutes of Health, RePORTER application 10373433, Mechanistic studies and therapeutics for ALS/FTD linked to UBQLN2 mutations (2RF1NS098243-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10373433. Licensed CC0.

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