# Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $543,000

## Abstract

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal
dementia (FTD) are increasing public health challenges, for which effective treatment is still
lacking. At least two major themes have emerged from the studies of ALS/FTD, concerning
etiology related to both RNA metabolism and protein homeostasis. However, the RNA- and
protein-based pathogenesis are likely to be interdependent. Here we propose to unravel the key
molecular pathways in the common pathogenic processes at the intersection of RNA and
protein homeostasis. FUS is one of the RNA-binding proteins that have linked to ALS/FTD.
Recently, we discovered a new role for RNA-binding proteins, as exemplified by FUS, in the
direct regulation of the activities of microRNAs, which are small RNAs functioning as critical
regulators of gene expression. Moreover, considering the notion that FUS protein is capable of
undergoing phase separation, assembling into stress granules, and forming protein aggregates,
and building on our preliminary evidence, we propose to elucidate the previously unrecognized
mechanisms through which aberrant formation of stress granules and protein aggregates
disrupt the RNA homeostasis maintained by ALS/FTD associated proteins. Furthermore, our
studies will be directed at uncovering the cellular quality control systems that are built in to
maintain the RNA/protein homeostasis and understanding how these systems go awry in
diseases. Our unique potential to contribute to this field is both conceptual and technical: We
have developed a unique combination of biochemical/C. elegans/mammalian systems to study
the mechanisms of neurodegeneration, and our recent success bodes well for future plans. The
findings will not only provide novel understandings of the molecular causes of disease for key
ALS genes but also suggest new strategies for harnessing the cellular defense system to
prevent and treat the relevant forms of ALS and other related neurodegenerative diseases. We
predict that the advances gained through our research efforts will eventually lead to new
therapeutic interventions to address these devastating diseases.

## Key facts

- **NIH application ID:** 9851958
- **Project number:** 5R01NS110098-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jiou Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $543,000
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851958

## Citation

> US National Institutes of Health, RePORTER application 9851958, Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2 (5R01NS110098-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851958. Licensed CC0.

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