The c9orf72 Complex in Frontotemporal Degeneration (FTD) Drug Discovery
Abstract
Neurodegenerative disorders place a vast emotional and financial burden on society, yet both preventative and curative strategies are lacking. Frontal temporal dementia (FTD) and the related disease amyotrophic lateral sclerosis (ALS) are incurable neurodegenerative diseases that lead to changes in behavior, cognition, and personality; and loss of muscle movement, respectively. In most cases, the causes of FTD and ALS are unknown. The best clue that exists to the cause of FTD is that mutations in the C9ORF72 gene are the most frequent genetic cause of both hereditary FTD and ALS. C9ORF72 gene mutations have several harmful effects on neurons, including a reduction in the amount of C9orf72 protein. Decreasing levels of C9orf72 protein leads to decreasing amounts of a healthy cellular cleansing pathway known as autophagy, or cellular self-eating. This proposal is based on the hypothesis that autophagy is defective in all FTD, not just hereditary FTD, and that all FTD patients should therefore benefit from increasing neuronal autophagy. It has been shown that using molecular biology to restore healthy levels of C9orf72 protein can rescue cultured neurons with C9ORF72 mutations from death. In order to do the same thing in patients, this project seeks to discover drug-like small molecules that stabilize the residual levels of C9orf72 protein in neurons, and so increase the amount of autophagy to near normal levels. This will be done by determining the structure and the small molecule binding properties of the C9orf72 protein complex, i.e., the combination of C9orf72 with the other proteins with which it normally associates in cells. The small molecules will be studied in cells to confirm their properties. Actually turning these small molecules into drugs will take longer and be more expensive and is not part of this proposal. This proposal is an exploratory effort to determine if the concept is valid and warrants investment in a full-fledged drug discovery program.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010086
Entities
People
- James H. Hurley
Organizations
- United States Army
- University of California, Berkeley