# Disruption of nucleocytoplasmic transport in FUS-related neurodegenerative diseases

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $86,783

## Abstract

Impaired nucleocytoplasmic transport (NCT) of protein and RNA through the nuclear pore has recently emerged
as a central mechanism in neurodegeneration. Indeed, we have recently shown that mutant huntingtin markedly
exacerbates aging-related alterations in nuclear integrity and disruption of NCT, and defects in nuclear pore-mediated
transport have also been uncovered in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia
(FTD). Here, we demonstrate that expression of mutant FUS, a protein linked to ALS and FTD, leads to a loss of nuclear
pore integrity, altered nuclear envelope morphology and other phenotypes related to disrupted NCT in multiple, relevant
models including isogenic human neurons and a novel FUS knock-in mouse model. In this project, we will further
interrogate the relationship between disease-associated FUS and impaired NCT in ALS and FTD using the
aforementioned model systems and human CNS tissues (Aim 1). To elucidate the mechanism by which expression of
mutant FUS induces NCT-related phenotypes, we will further probe the interactions between FUS and nuclear pore
proteins, and test the hypothesis that abnormal phase transitions involving mutant FUS and nuclear pore proteins
contribute to disrupted NCT (Aim 2). We also posit that impaired NCT induces toxicity via the mislocalization of
transcripts and proteins, a notion that will be tested by using RNA-sequencing and proteomics to compare gene expression
after cellular fractionation in mutant FUS versus control neurons, before and after manifestation of NCT-related
phenotypes (Aim 3). Finally, we will test the therapeutic potential of targeting nuclear export in FUS human neurons and
mice using strategies that have already been shown to be both safe and effective across multiple human diseases (Aim 4).
This synergistic collaboration between two academic groups and an industrial partner (who will provide the therapeutic
compound for studies in our laboratories) has the potential to uncover new mechanistic insights to disease and establish
the therapeutic potential of targeting nucleocytoplasmic transport in ALS/FTD.

## Key facts

- **NIH application ID:** 10387048
- **Project number:** 3R01NS108769-03S1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Daryl Angela Bosco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $86,783
- **Award type:** 3
- **Project period:** 2019-05-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387048

## Citation

> US National Institutes of Health, RePORTER application 10387048, Disruption of nucleocytoplasmic transport in FUS-related neurodegenerative diseases (3R01NS108769-03S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10387048. Licensed CC0.

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