Dipeptide repeat proteins inhibit homology-directed DNA double strand break repair in C9ORF72 ALS/FTD
Abstract
The C9ORF72 hexanucleotide repeat expansion is the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two fatal age-related neurodegenerative diseases. The C9ORF72 expansion encodes five dipeptide repeat proteins (DPRs) that are produced through a non-canonical translation mechanism. Among the DPRs, proline-arginine (PR), glycine-arginine (GR), and glycine-alanine (GA) are the most neurotoxic and increase the frequency of DNA double strand breaks (DSBs). While the accumulation of these genotoxic lesions is increasingly recognized as a feature of disease, the mechanism(s) of DPR-mediated DNA damage are ill-defined and the effect of DPRs on the efficiency of each DNA DSB repair pathways has not been previously evaluated.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 24, 2020
- Source ID
- 10.1186/s13024-020-00365-9
Entities
People
- Abbas Abdallah
- Christian Mueller
- Claes Wahlestedt
- Gabriel Gaidosh
- Mathew J. Rybin
- Melina Ramic
- Michael Benatar
- Nadja S. Andrade
- Nancy T. Chee
- Rustam Esanov
- Sadhana Anatha
- Samuel Del’olio
- Tania F. Gendron
- Tyler C. Huff
- Wenjun Liu
- Yanbin Zhang
- Zane Zeier
Organizations
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health
- United States Department of Defense