# Mitigation of nuclear pore dysfunction in c9FTD/ALS pathogenesis

> **NIH NIH P01** · SCRIPPS FLORIDA · 2020 · $259,424

## Abstract

PROJECT SUMMARY/ABSTRACT 
A GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of 
frontotemporal dementia (FTD) and familial amyotrophic lateral sclerosis (ALS), and the mutation is frequently 
seen in apparent sporadic patients. The underlying mechanisms by which the C9ORF72 HRE causes 
“c9FTD/ALS” are poorly defined. Multiple studies, including our own, support a gain-of-function mechanism of 
neurotoxicity mediated by the HRE. Expanded repeats may generate toxic RNAs that sequester RNA-binding 
proteins. They may also be translated via repeat-associated non-ATG (RAN) translation into toxic “c9RAN 
proteins” of repeating dipeptides. Furthermore, multiple studies from our lab and others suggest that disruption 
of the nuclear pore and/or nucleocytoplasmic transport is a primary cause of neurodegeneration in yeast, fly, 
and induced pluripotent stem (iPS) cell models of c9FTD/ALS. In addition, our recent use of c9FTD/ALS iPS 
cell-derived neurons (iPSN) suggests they are a valuable and highly relevant preclinical model to uncover 
candidate therapies. This proposal will investigate the mechanism by which the C9ORF72 HRE disrupts 
nucleocytoplasmic transport and nuclear pores utilizing complementary models, which will include c9FTD/ALS 
iPSN and patient brain tissues, as well as brain tissue from (G4C2)66 mice (generated by Project 2), an in vivo 
model that recapitulates behavioral and neuropathological features of c9FTD/ALS. Our data suggest the 
defects in nucleocytoplasmic transport are fundamental events coupled with neurodegeneration in c9FTD/ALS. 
The proposed studies, first in iPSN and then validated in vivo with Project 2, will establish whether candidate 
therapies emerging from Project 1 are able to mitigate such detrimental defects. First, we will comprehensively 
investigate nuclear pore complex (NPC) function and pathology in c9FTD/ALS iPSN and rodent models. These 
experiments will define the specific role of NPC components in c9FTD/ALS pathophysiology and highlight 
targets worthiest of experimental manipulation or monitoring for molecular efficacy. Findings from these studies 
will guide our efforts to identify therapeutic strategies that mitigate nuclear pore dysfunction and pathology in 
c9FTD/ALS iPSN and rodent models. Such strategies will include genetic expression of selected nucleoporins 
or other mediators of nucleocytoplasmic transport (e.g. RanGAP1), and r(G4C2)exp-binding small molecules 
from Project 1. Finally, we will identify therapeutic strategies that rescue the heightened susceptibility of 
c9FTD/ALS iPSN to cellular stressors. C9ORF72 HRE toxicity may occur via disruption of NPC function and 
other events distal to the mutation that impair cellular function. These studies will provide a fundamentally 
important general readout of the therapeutic benefit of blocking HRE toxicity using r(G4C2)exp-binding small 
molecules or manipulating other mechanistic targets identified as...

## Key facts

- **NIH application ID:** 9962907
- **Project number:** 5P01NS099114-04
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Jeffrey D Rothstein
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $259,424
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962907

## Citation

> US National Institutes of Health, RePORTER application 9962907, Mitigation of nuclear pore dysfunction in c9FTD/ALS pathogenesis (5P01NS099114-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962907. Licensed CC0.

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