# NUP50 as a modifier and risk factor for TDP-43 pathology in FTD/ALS

> **NIH NIH R21** · MAYO CLINIC  JACKSONVILLE · 2023 · $430,267

## Abstract

The cytoplasmic mislocalization and accumulation of insoluble and misfolded RNA-
binding protein TDP-43 is the neuropathological hallmark of the amyotrophic lateral sclerosis (ALS) and
frontotemporal dementia (FTD) disease spectrum but is also commonly found in Alzheimer’s disease (AD) and
other AD-related dementias (ADRDs), marking TDP-43 mislocalization as a key pathomechanism and high
priority target for therapy development.
 Previous studies from our lab and others have established nuclear pore defects and impaired protein import
and RNA export, as a common hallmark of FTD/ALS and other age-related neurodegenerative diseases. While
there is growing evidence that perturbations in the nucleocytoplasmic transport machinery are linked to TDP-43
pathology, the causal relationship between intracellular transport pathways and disease pathogenesis is not well
understood. As prior research to support the premise of this proposal, we have discovered that expression
of the nucleoporin NUP50 in FTD/ALS models can restore solubility and nuclear localization of TDP-43,
suggesting an important role for NUP50 in the disease process. This premise is further supported by the recent
discovery of rare NUP50 variants as a risk factor for ALS, and a critical role for NUP50 in neuronal survival.
These findings lead us to hypothesize that NUP50 serves in a non-canonical role in reducing protein
mislocalization and aggregation, while its deficiency in FTD/ALS may lead to increased TDP-43 pathology,
suggesting NUP50 as a promising target for therapy development.
 To test this hypothesis, we will use TDP-43 cellular, organotypic and animal models, patient-derived and
induced pluripotent stem cell (iPSC)-derived neurons, in combination with mass spectrometry (MS)-based
quantitative proteomics and immunohistochemistry in human brain tissue, to elucidate how NUP50 can reduce
TDP-43 pathology, and how ALS/FTD-associated mutations in NUP50 contribute towards TDP-43 pathology.
 In Aim 1 we will methodically investigate the effect of NUP50 on aberrant TDP-43 phase transition and
mislocalization and establish the role of structural domains and associated proteins for a mechanistic
understanding of this activity in vitro. In Aim 2 we will determine the effect of NUP50 on TDP-43-dependent
neurodegeneration in FTD/ALS mouse models, to evaluate NUP50 and associated proteins as a potential
therapeutic targe in vivo. In Aim 3, we will establish the role of NUP50 in human TDP-43 proteinopathies, by
testing the effect of NUP50 deficiency and disease-associated NUP50 variants on TDP-43 pathology and
assessing the abundance and localization of NUP50 in FTD/ALS and ADRD autopsy brain tissue.
 Our findings will impact the field by providing a detailed mechanistic understanding of how NUP50 expression
can impact TDP-43 pathology in disease models, and by establishing the role of NUP50 in the disease process
and validating it as a potential therapeutic target in FTD/ALS and other ADRDs.

## Key facts

- **NIH application ID:** 10800366
- **Project number:** 1R21AG085314-01
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Wilfried Rossoll
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $430,267
- **Award type:** 1
- **Project period:** 2023-09-30 → 2025-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800366

## Citation

> US National Institutes of Health, RePORTER application 10800366, NUP50 as a modifier and risk factor for TDP-43 pathology in FTD/ALS (1R21AG085314-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10800366. Licensed CC0.

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