# Mechanisms of nuclear pore complex homeostasis and injury in ALS/FTD and related neurodegenerative diseases

> **NIH NIH R00** · JOHNS HOPKINS UNIVERSITY · 2024 · $249,000

## Abstract

PROJECT SUMMARY
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) comprise a spectrum of devastating
and fatal neurodegenerative diseases. While over 20 genetic loci have been linked to ALS and FTD, about
90% of ALS cases are sporadic in nature. Recent studies have identified alterations in the nuclear pore
complex (NPC) and nucleocytoplasmic transport (NCT) as a prominent pathomechanism underlying familial
and sporadic ALS. However, the molecular mechanisms underlying these pathologic disruptions remain largely
unknown. Our recent studies have established that there is a reproducible and robust reduction of eight
nucleoporins (Nups) from the NPC in C9orf72 iPSN and postmortem patient neuronal nuclei. Recent work
suggests that the ESCRT-III pathway plays a fundamental role in the surveillance and maintenance of properly
assembled and functioning NPCs in yeast. Critically, work in these non-CNS systems suggests that
recruitment of CHMP7 to the nuclear envelope initiates downstream events leading to degradation of Nups and
NPCs. Indeed, the reduction of Nups from the NPC in C9orf72 human neurons appears to be the result of
aberrant activation of CHMP7 and ESCRT-III mediated degradation pathways and not the result of Nup
mislocalization or alterations in Nup mRNA metabolism. However, little is actually known about how these
initial discoveries relate to the far more common sporadic ALS (sALS). Using super resolution structured
illumination microscopy (SIM) on a subset of sALS iPSC derived spinal neurons, we have generated
preliminary data that strongly suggests NPC and Nup defects are a prevalent pathology in sALS. Notably, in
about 50% of sALS iPSNs and postmortem motor cortex samples examined to date, we also observe robust
CHMP7 pathology, reminiscent of our studies in C9orf72 ALS/FTD. Collectively, these early studies have led
us to hypothesize that in human neurons, aberrant activation of the ESCRT-III pathway may be a substantial
contributor to disruptions in the NPC, NCT, and overall cellular survival thus highlighting the potential for
CHMP7 as a therapeutic target in ALS and related neurodegenerative diseases characterized by NPC injury.
Here, we will use iPSNs and postmortem human CNS tissue to comprehensively define the alterations to
individual Nups and NPCs in sALS pathogenesis (Aim 1). Furthermore, we will evaluate the contribution of
CHMP7 and aberrant ESCRT-III mediated degradation to NPC injury in sALS (Aim 2). Finally, we will define
the mechanism by which CHMP7 is pathologically “activated” to initiate NPC injury in sALS (Aim 3).
Collectively, these experiments will significantly advance our understanding of the mechanisms underlying
NPC homeostasis in human neurons and sALS disease and provide novel insights into potential new
therapeutic targets. Moreover, the proposed studies will set the stage for future investigations into the role of
CHMP7 and Nup degradation in the pathogenesis of FTD and other related n...

## Key facts

- **NIH application ID:** 10872258
- **Project number:** 5R00NS123242-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Alyssa Coyne
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2021-07-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872258

## Citation

> US National Institutes of Health, RePORTER application 10872258, Mechanisms of nuclear pore complex homeostasis and injury in ALS/FTD and related neurodegenerative diseases (5R00NS123242-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10872258. Licensed CC0.

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