A Novel Therapeutic Target for Wide-Spectrum Antiproteotoxicity Effects in ALS
Abstract
Amyotrophic lateral sclerosis (ALS or Lou Gehrig s disease) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Proteotoxicity is a central and common theme in many forms of ALS. Unfortunately, the mechanisms underlying this motor neuron degenerative disease remain poorly understood and currently there is no effective therapy. Recent advances in understanding the perturbation of protein homeostasis as a common theme in ALS point to new directions in therapeutic interventions. Although both RNA and protein metabolisms are implicated in ALS pathogenesis, the single most common thread for ALS genes is the involvement of protein misfolding and aggregation, including many ALS-related proteins. In therapeutic development, the strategy of targeting single disease protein is often complicated by the side effects of losing its critical cell functions. To overcome the limitation, we have resorted to unbiased searches for robust suppressors of protein aggregation. Over the years, we have developed tractable genetic models of proteotoxicity for ALS, and through large-scale screens, identified strong suppressors of neurotoxicity associated with misfolded ALS proteins. Remarkably, in-depth investigations of these suppressor genes revealed previously unrecognized pathways robustly boosting protein quality control in human cells. Importantly, top suppressor genes identified from independent screens converge on specific transcription factor switches, suggesting a reprogramming of protein quality control. In this project, we hope to establish novel therapeutic strategies by validating wide-spectrum protective chemical agents on preclinical models based on our recent findings of strong modifiers of protein quality control. The proposed research, if successful, will provide strong preclinical evidence for the effectiveness of novel therapeutic targets that we expect to be promising candidates for further evaluation in human ALS clinical trials in the next few years. The work has a significant chance of generating new therapies for ALS and will benefit both inherited and sporadic ALS patients. In a long-term view, our research will also highlight a new paradigm for antagonizing proteotoxicity-associated neurodegeneration, i.e., harnessing the protective capacity of protein quality controls in the cell. Our discovery platform for novel proteotoxicity suppressors can then be applied to future ALS studies and ultimately help us to better treat or prevent this devastating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910311
Entities
People
- Jiou Wang
Organizations
- Johns Hopkins University
- United States Army