# Cellular and Molecular Mechanisms of FUS-related ALS/FTD

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $385,976

## Abstract

ALS is a late-onset progressive neurodegenerative disease caused by degeneration of motor
neurons, and a disease hallmark is the accumulation of ubiquitin-positive aggregates in
neuronal cytoplasm. FUS was identified as genes mutated in both familial and sporadic forms of
ALS. In fact, a subset of patients with frontotemporal dementia (FTD) show FUS pathology.
FUS, similar to TDP-43, is an RNA binding protein implicated in multiple aspects of RNA
metabolism, including splicing, trafficking, and translation. The precise mechanisms of mutated
FUS in ALS pathogenesis are not known.
To understand the molecular mechanisms of FUS-mediated neurodegeneration, we developed
cellular (mammalian primary neuronal and patient-derived iPSC motor neuron) and Drosophila
models that recapitulate key features of human disease including cytoplasmic mislocalization,
neuromuscular junction defects, locomotor dysfunctions, reduced life span, perturbed stress
granule dynamics and toxicity. We discovered muscleblind and drosha as unexpected and novel
modifiers of mutant FUS toxicity. MBNL proteins, highly conserved from lower organisms to
vertebrates, have been implicated in many neurodegenerative disorders, such as myotonic
dystrophy and CAG repeat diseases. The long-term goal is to identify modifiers of FUS toxicity
and understand their molecular mechanisms using mammalian cell culture and Drosophila
models. The objective of our current application is to determine how muscleblind and drosha
modulate FUS-mediated toxicity in Drosophila and FUS iPSC motor neurons. We hypothesize
that muscleblind and drosha regulate RNA splicing, SG dynamics and miRNA biogenesis that is
perturbed by pathogenic mutations in FUS. We will examine the impact of muscleblind and
drosha on cellular and molecular pathologies in FUS-associated neurodegeneration. We expect
to dissect the molecular pathways that could be exploited for developing therapeutic
interventions for ALS/FTD patients.

## Key facts

- **NIH application ID:** 10137320
- **Project number:** 5R01NS081303-08
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Udai B Pandey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,976
- **Award type:** 5
- **Project period:** 2013-04-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137320

## Citation

> US National Institutes of Health, RePORTER application 10137320, Cellular and Molecular Mechanisms of FUS-related ALS/FTD (5R01NS081303-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10137320. Licensed CC0.

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