# Investigating how nuclear pore components exploit an ER-dependent quality control pathway

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $38,167

## Abstract

Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily targets motor
neurons, leading to progressive muscle weakness and paralysis. There is no cure for ALS or the
related disorder frontotemporal dementia (FTD), largely because it is unclear which of the many
implicated cellular pathways are causative. A growing number of studies have identified damage to
the nuclear pore complex (NPC) as a key pathological phenotype in both ALS-diseased tissue and
ALS models. This damage is characterized by defective nucleocytoplasmic transport and
mislocalization of NPC components (“Nups”) to the cytosol.
To examine the fate of mislocalized Nups, our research group has developed a model for NPC
disruption whereby we deplete a key structural Nup and track the localization of other Nups.
Strikingly, our preliminary data shows that the displaced Nups form aggregates in the endoplasmic
reticulum, a process which is dependent on the ER transmembrane protein kinectin. These
aggregates accumulate upon depletion of the major autophagy factor Beclin-1, suggesting that the
Nups are targeted for ER-coupled autophagy. Together, these findings point to a novel nucleus-to-ER
autophagy pathway that may be functioning when Nups are displaced in ALS. Based on this
preliminary data, we hypothesize that the cellular motor protein kinesin-1 transports Nups from the
nucleus to the ER (Aim 1A), and that this transport process also occurs in a disease-relevant cell
culture model (Aim 1B). We further hypothesize that once at the ER, the Nup aggregates are cleared
by receptor-mediated autophagy (Aim 2). This work will elucidate basic intracellular trafficking and
quality control pathways. More importantly, understanding cellular response to mislocalized Nups
may provide a better mechanistic picture of the progression of ALS/FTD.

## Key facts

- **NIH application ID:** 10463580
- **Project number:** 5F31NS124088-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Madison Lynn Pletan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,167
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463580

## Citation

> US National Institutes of Health, RePORTER application 10463580, Investigating how nuclear pore components exploit an ER-dependent quality control pathway (5F31NS124088-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10463580. Licensed CC0.

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