# Mechanisms of Novel Regulators of Proteotoxicity and Quality Control Associated with ALS/FTD

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $537,477

## Abstract

Project Summary
 Neurodegeneration is an increasing public health challenge and remains an unsolved
biomedical problem. Protein misfolding and aggregation are a central feature of
neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal
dementia (FTD). The complexity of neurodegeneration calls for large-scale unbiased screening
studies. Over the past few years, we have made breakthrough observations with significant
implications for understanding the cellular defense systems against proteotoxicity underlying
pathogenesis in ALS/FTD. Using a unique blend of genetic, biochemical, and cell biological
approaches, we have uncovered novel pathways that enable reprogramming of protein quality
control to counter proteotoxicity. The newly proposed work in this project is aimed at elucidating
mechanisms underlying newly identified regulators and master switches in protein quality
control. The studies on the previously unrecognized higher-order regulators could expand our
understanding of proteotoxic-stress-responsive quality control systems in the cell, beyond the
well-established heat shock response or unfolded protein response. Our unique abilities to
contribute to this field are at both conceptual and technical levels: In additional to novel
pathways, we have developed unique C. elegans/mammalian reporter systems to study
proteotoxicity-associated neurodegeneration, and our recent success bodes well for future
plans. Furthermore, our expanding repertoire of tools will allow us to extend the findings to
diverse models and patient cells. The specific aims are to elucidate the mechanisms through
which a novel conserved pathway, involving a previously unknown transcriptional master switch,
in the regulation of protein quality control, to delineate the pathways through which a novel
target and its signaling pathway regulate proteotoxicity, and to develop new tools for more
advanced search for key regulators of proteotoxicity and quality control. The findings will not
only provide novel entry points for understanding the toxicities of key ALS/FTD proteins, such as
SOD1, TDP-43, and C9orf72 DPRs, but also reveal molecular targets for harnessing the cellular
defense system to prevent and treat the relevant neurodegenerative diseases. We predict that
the advances gained through our research efforts will eventually lead to new therapeutic
interventions to address these diseases in the world’s rapidly aging population.

## Key facts

- **NIH application ID:** 10130729
- **Project number:** 2R01NS074324-11
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jiou Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $537,477
- **Award type:** 2
- **Project period:** 2011-08-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130729

## Citation

> US National Institutes of Health, RePORTER application 10130729, Mechanisms of Novel Regulators of Proteotoxicity and Quality Control Associated with ALS/FTD (2R01NS074324-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130729. Licensed CC0.

---

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