# Nucleocytoplasmic transport and nuclear pore disruption in ALS/FTD

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $653,024

## Abstract

PROJECT SUMMARY
A GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of
familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), though the underlying disease
mechanism is 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 Translation (RANT) into toxic dipeptide
repeat proteins (DPRs). Both HRE RNA and DPRs are hypothesized to mediate neurotoxicity in C9-ALS/FTD.
Multiple recent 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 cell
(iPS) models of C9- ALS/FTD. In addition, our recent studies, using a C9-ALS/FTD Drosophila model, human
iPS neurons derived from C9-ALS patients, and human C9-ALS CNS tissues, suggest that nucleocytoplasmic
transport defects may be a fundamental pathway for ALS/FTD pathogenesis amenable to therapy.
This proposal will comprehensively investigate the mechanism by which the C9ORf72 HRE disrupts
nucleocytoplasmic transport and nuclear pores utilizing several complementary models including C9-ALS fly
and mouse models and iPS neurons and brain tissue from C9 ALS/FTD patients, and investigate whether
modulation of nucleocytoplasmic transport may be a therapeutic strategy for ALS/FTD. (1) We will determine
the morphological and biochemical composition of the nuclear pore complex (NPC) in motor neurons and glia,
and characterize NPC pathology in C9-ALS/FTD in fly, iPS, mouse models and human brain. Little is known
about CNS NPCs including differences between cell types and ultimately how the NPC constituents,
nucleoporins, are dysregulated in C9-ALS/FTD models. Therefore, understanding the basic characteristics of
the NPC and nucleocytoplasmic transport in the CNS and in disease models is fundamentally important to
dissecting the nature of pathology. (2) We will then investigate the mechanism of nucleocytoplasmic transport
disruption in C9-ALS/FTD. We hypothesize that disrupted NPC and/or nucleocytoplasmic transport function
causes neurodegeneration due to nuclear loss and/or cytoplasmic accumulation of nuclear export sequence
(NES) containing cargo in fly, mouse, and iPS models of C9-ALS. (3) Therefore, we will determine the
consequences of nucleocytoplasmic transport disruption in C9-ALS/FTD models. (4) Finally, we will determine
if restoration of nucleocytoplasmic transport rescues neurodegeneration in C9-ALS/FTD by employing a series
of novel compounds that may have human utility.

## Key facts

- **NIH application ID:** 9896868
- **Project number:** 5R01NS094239-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Thomas E. Lloyd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $653,024
- **Award type:** 5
- **Project period:** 2016-06-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896868

## Citation

> US National Institutes of Health, RePORTER application 9896868, Nucleocytoplasmic transport and nuclear pore disruption in ALS/FTD (5R01NS094239-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896868. Licensed CC0.

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