# Abnormal Matrin 3 turnover and nucleic acid-binding in ALS and related disorders

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $25,679

## Abstract

PROJECT SUMMARY
 Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the
loss of upper and lower motor neurons, leading to paralysis and death. Despite decades of research, there are
still no disease-altering therapies for patients with ALS. Accumulating evidence implicates RNA-binding protein
(RBP) dysfunction as a key feature in the pathogenesis of ALS and related disorders such as frontotemporal
dementia (FTD). Notably, the vast majority (>95%) of individuals with ALS display cytoplasmic mislocalization
and aggregation of the RBP TDP-43 (transactive response element DNA/RNA-binding protein, 43 kDa) in
affected tissue. In addition, mutations in the genes encoding TDP-43 and other RBPs cause disease. Several
of these RBPs, including the nuclear matrix protein Matrin 3 (MATR3), are implicated not only in combined
ALS/FTD, but also myopathy. MATR3 mutations are responsible for familial ALS, FTD, and myopathy, and
post-mortem studies demonstrated MATR3 aggregation and mislocalization in sporadic disease patients who
lack any identifiable mutations, suggesting that MATR3 dysregulation may have a conserved pathogenic role in
both sporadic and familial disease. Despite this, little is known about MATR3 function, how it might be
disrupted in disease, and the effects of pathogenic mutations on MATR3 behavior.
 This proposal seeks to expand our understanding of MATR3 and its contribution to disease. I previously
established a neuronal model of MATR3-mediated neurodegeneration and used this model to highlight the
importance of MATR3 nucleic acid binding and nucleocytoplasmic localization in disease. I also identified a
subset of pathogenic MATR3 mutations that affect protein solubility and dynamics. Here, I will build upon this
work by testing the hypothesis that disease-associated MATR3 mutations result in neurodegeneration by
impacting MATR3 turnover and its DNA/RNA-binding properties. These studies may reveal new mechanisms
underlying MATR3-mediated toxicity in ALS and related disorders, with broad relevance not only for rare
familial disease due to MATR3 mutations but also for sporadic disease. Additionally, it will offer me the
opportunity to develop essential skills in hypothesis testing, experimental design, data analysis, and scientific
communication that will be critical for success in my intended career as a physician-scientist in the field of
neurological disease.

## Key facts

- **NIH application ID:** 9949378
- **Project number:** 5F31NS110119-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ahmed Mughees Malik
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $25,679
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949378

## Citation

> US National Institutes of Health, RePORTER application 9949378, Abnormal Matrin 3 turnover and nucleic acid-binding in ALS and related disorders (5F31NS110119-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9949378. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*