# Investigation of UBQLN2 in neuronal dysfunction and ALS-FTD

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2024 · $580,593

## Abstract

Amyotrophic Lateral Sclerosis with frontotemporal dementia (ALS-FTD) is a progressive, fatal
neurodegenerative disease that results from the loss of upper and lower motor neurons, as well as neurons of
the frontal cortex. The resulting symptoms of ALS-FTD are progressive motor and cognitive impairment. Little is
known about the underlying mechanism of disease, and there are no effective treatments that significantly
lengthen lifespan. 10% of ALS-FTD cases show a familial pattern of inheritance and can often be traced to
mutation of specific genes. Familial ALS-FTD (fALS-FTD) shares key features with sporadic ALS-FTD, meaning
that the study of fALS-FTD can provide broadly applicable findings in the fight against this devastating disease.
 Mutations in the human UBQLN2 gene lead to a portion of fALS-FTD cases, but the mechanism of
disease is poorly understood. UBQLNs are a family of proteasome shuttle factors which facilitate proteasomal
degradation of ‘difficult’ proteasome substrates, though the identity of these substrates has been elusive. We
recently published that UBQLN2 regulates proteasomal degradation of the protein PEG10. PEG10, or ‘paternally
expressed gene 10’, is a ‘domesticated retrotransposon’: it resembles retrotransposons and retroviruses in its
overall structure, but is unable to transpose within the genome. Like its viral cousins, the PEG10 protein contains
a nucleic-acid binding zinc finger and a protease domain, both with unknown function. We recently discovered
that PEG10 is an active self-protease and releases a protein fragment containing the nucleic acid-binding region
which then traffics to the nucleus. Expression of this fragment alone is sufficient to upregulate expression of
genes involved in axon remodeling, which are similarly upregulated in ALS-FTD tissues. Therefore, PEG10 is
an excellent candidate for the molecular cause of ALS-FTD upon UBQLN2 dysfunction. In our model, UBQLN2
loss or dysfunction leads to PEG10 accumulation, increased liberation of the nucleic acid-binding fragment, and
upregulated axon remodeling genes, leading to phenotypes of disease. This proposal seeks to validate and
explore our new model of disease in depth with a complement of in vitro and in vivo approaches.
 Our goals for the next five years are to generate a deep understanding of the UBQLN2-PEG10
relationship and how it influences the development of ALS-FTD. In our first Aim, we carefully examine the
abundance and proteolytic activity of PEG10 in ALS and FTD patient tissue. In our second Aim, we determine
the mechanism and precise contribution of PEG10 in cellular and animal models of UBQLN2-mediated disease.
Finally, we dive deeply into the molecular underpinnings of UBQLN2-PEG10 interactions in order to generate
the first detailed model for UBQLN client selection. The findings from our research program will transform our
basic understanding of PEG10 function as well as UBQLN2 biology, and may provide crucial new targets for the
fight a...

## Key facts

- **NIH application ID:** 10868497
- **Project number:** 5R01NS131660-02
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Alexandra Whiteley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $580,593
- **Award type:** 5
- **Project period:** 2023-06-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868497

## Citation

> US National Institutes of Health, RePORTER application 10868497, Investigation of UBQLN2 in neuronal dysfunction and ALS-FTD (5R01NS131660-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10868497. Licensed CC0.

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