# Mechanisms of FUS Toxicity in Animal and Cellular Models of ALS/FTD.

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $648,000

## Abstract

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder in which preferential loss of
motor neurons (MNs) results in paralysis and death. Although ALS is largely a sporadic disease, research has
focused on heritable forms of the disorder because clinical and pathological evidence suggests common
pathogenic mechanisms. Mutations in the gene FUS cause some of the most aggressive early-onset forms of
ALS. FUS pathology – and rarely, mutations - are also associated with the related neurodegenerative disorder,
frontotemporal dementia (FTD). In a recent study, our lab demonstrated in a mouse model of disease that mutant
FUS causes motor neuron degeneration not by a loss-of-function, by a toxic gain-of-function that does not involve
an excess of FUS activity. FUS is one of a number of RNA binding proteins – including TDP-43 and hnRNP
A1 – that have been causally related to ALS and FTD. Recent work has led to a disease model in which the
intrinsically disordered “prion-like” domain of FUS and related proteins drives a phase transition that results in
the formation of an irreversible, neurotoxic aggregate. ALS-related mutations in FUS increase the natural
tendency of the protein to form these toxic assemblies, which trap and sequester other ribonucleoprotein granule
components. In this project we will explore the mechanisms of FUS toxicity in a novel series of knock-in mutant
mice that reproduce key aspect of the FUS-ALS phenotype. In addition, in vitro studies using motor neurons
and astrocytes derived from these mouse models will be used to investigate cell autonomous and non-
autonomous mechanisms of disease. In Aim 1, we will use a conditional knock-in mouse model to express
mutant FUS in MNs or astrocytes, or more broadly in the nervous system to explore the effects of temporally
and spatially regulated mutant FUS expression on MN survival and function; and we will also explore the relative
toxicity of human FUS in a fully humanized mouse model of FUS-ALS. In this highly disease-relevant model of
ALS/FTD, we will also test the therapeutic potential of the FUS disaggregase, Kap2 as a means to slow or stop
the onset and progression of MN degeneration. In Aim 2, we will combine sophisticated electrophysiological and
behavioral methods to explore the functional consequence of mutant FUS throughout disease progression in the
FUS knock-in mouse. Finally in Aim 3, we will apply a combination of single-cell RNA sequencing and topological
data analysis to a mixed distribution of in vitro differentiated MNs derived from our FUS knock-in mutant mice.
This sophisticated integration of in vivo and in vitro experimental systems, combined with our integrative
computational and analytical approach will allow us to elucidate pathways of disease in vulnerable
subpopulations of MNs and to identify potential therapeutic targets for the treatment of FUS-ALS and related
forms of motor neuron disease.

## Key facts

- **NIH application ID:** 9948011
- **Project number:** 5R01NS106236-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Neil Alan Shneider
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $648,000
- **Award type:** 5
- **Project period:** 2019-06-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948011

## Citation

> US National Institutes of Health, RePORTER application 9948011, Mechanisms of FUS Toxicity in Animal and Cellular Models of ALS/FTD. (5R01NS106236-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948011. Licensed CC0.

---

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