# FG-nucleoporins and nuclear transport disruption in C9ORF72-ALS/FTD

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2021 · $199,800

## Abstract

PROJECT SUMMARY/ABSTRACT
The GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 (C9) is the most common known cause of
amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including familial and sporadic forms
of the disease, as well as the ALS/FTD overlap syndrome. The C9 HRE is thought to cause disease by a toxic
gain of function, mediated by expanded repeat RNAs and/or dipeptide repeat proteins (DPRs), produced by
aberrant translation of the HRE. Our laboratory and others recently discovered that the C9 HRE impairs
nucleocytoplasmic transport across multiple species and model systems, strongly implicating this fundamental
cellular pathway in C9-mediated neurodegeneration. Our more recent, unpublished data suggest that the
mechanism of nuclear transport impairment in C9-ALS/FTD involves disruption of a subset of nucleoporin
proteins (Nups) with low complexity phenylalanine-glycine domains (FG-Nups). In yeast, FG-Nups line the
nuclear pore complex (NPC), playing key roles in transport specificity and permeability, and a subset are
functionally essential for nuclear transport and cell survival. Currently, little is known about the biology of FG-
Nups in mammalian cells, particularly in the central nervous system (CNS), posing a major barrier for
understanding the consequences of FG-Nup disruption in C9-ALS/FTD. In the proposed studies, our goal is to
comprehensively evaluate FG-Nup expression and function in ALS/FTD-vulnerable cells of the CNS, to serve
as a framework for further investigation of C9 toxicity. We will use the INTACT transgenic mouse (isolation of
nuclei tagged in specific cell types) to isolate nuclei from defined neuronal and glial populations, analyze the
expression and localization of FG-Nups by mass spectrometry and immuno-EM, and use siRNA knockdown to
identify which FG-Nups are essential for nuclear transport and cell survival. Subsequently, we will investigate
two potential mechanisms of C9-mediated FG-Nup disruption: (1) altered expression, and (2) cytoplasmic
mislocalization and aggregation, which may be triggered by aberrant protein-protein interactions between
DPRs and the FG-low complexity domain. Finally, we will test whether manipulating these factors in C9
induced pluripotent stem cell-derived neurons (iPSN) attenuates nuclear transport defects and prevents
neurotoxicity. Taken together, these studies will provide the first comprehensive assessment of FG-Nup
biology in ALS/FTD-vulnerable cells of the CNS, elucidate mechanisms by which C9 disrupts these essential
FG-Nups, and identify novel targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10237182
- **Project number:** 5K08NS104273-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Lindsey Renae Hayes
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $199,800
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237182

## Citation

> US National Institutes of Health, RePORTER application 10237182, FG-nucleoporins and nuclear transport disruption in C9ORF72-ALS/FTD (5K08NS104273-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10237182. Licensed CC0.

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