# Contribution of astrocytes to mutant FUS-linked Amyotrophic Lateral Sclerosis

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2022 · $341,250

## Abstract

ABSTRACT
The goal of this project is to identify the mechanisms by which mutations in Fused in
Sarcoma (FUS) induce pathological and pathogenic changes in astrocytes in FUS-linked
Amyotrophic Lateral Sclerosis (FUS-ALS).
Astrocytes are known to contribute to disease progression in some, but not all, forms of
ALS and, until recently, not much was known about the role of astrocytes in FUS-ALS.
Our lab has recently published the first in vitro evidence that astrocytes expressing
mutant forms of FUS (mutFUS), but not wild-type FUS, exert toxicity on motor neurons
through activation of the NFkB pathway leading to the release of secreted factor(s), and
primarily TNFα (Kia & McAvoy et al., GLIA, 2018). In a TNFα−dependent manner, motor
neurons exposed to the conditioned medium of mutFUS astrocytes show AMPA receptor
alterations that sensitize them to excitotoxic damage, leading to cell death. Activation of
astrocytic NFkB and TNFα release seems to be specific to mutFUS-ALS, underscoring
the importance of dissecting disease mechanisms specific to each form of ALS in order
to develop tailored therapies.
In this proposal, we will focus on mutFUS-ALS and will study (1) the mechanisms by
which disease-casuative mutations in FUS alter astrocyte biology and (2) how mutant
FUS expressing astrocyte affect the viability of other cells in the spinal cord in vivo. The
ultimate goal is to identify key pathways targeted by mutFUS to eventually develop
specific therapies. Ultimately, our models of FUS-ALS may serve as a platform for a
comparative analysis with models mimicking other forms of ALS, so to identify genotype-
specific vs. converging and more global mechanisms of disease pathogenesis. For our
studies, we will use in vitro and in vivo models consisting of (1) primary rodent astrocytes
transduced with different FUS mutations as well as iPSc-derived astrocytes from FUS
patients; (2) an in vivo mouse model of mutFUS ALS. The in vitro systems will allow us
to dissect the precise mechanisms by which mutFUS targets the astrocytes and to
determine how mutFUS alters astrocyte biology in patients. The mouse model will allow
us to study how mutFUS astrocytes affect the cellular environment in a complex in vivo
setting.

## Key facts

- **NIH application ID:** 10404651
- **Project number:** 5R01NS109150-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** PIERA PASINELLI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $341,250
- **Award type:** 5
- **Project period:** 2019-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404651

## Citation

> US National Institutes of Health, RePORTER application 10404651, Contribution of astrocytes to mutant FUS-linked Amyotrophic Lateral Sclerosis (5R01NS109150-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10404651. Licensed CC0.

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