Suppression of TDP-43 Proteinopathy in Mice by Targeting Rad-23
Abstract
Protein homeostasis (or proteostasis) is the balance of protein synthesis and protein degradation and is a requirement for optimally cellular functioning. The observation that misfolded proteins aggregate and accumulate in all neurodegenerative diseases is prime evidence that proteostasis has gone awry. Re-establishment of proteostasis is a major therapeutic goal. The identification of misfolded proteins and their targeting to the major degradative pathways (i.e., the proteasome or the autophagy pathway) are highly regulated processes. Rad23 was originally identified in a yeast screen for mutants that were hypersensitive to UV irradiation and subsequent shown to play a critical role in the ubiquitin- proteasome system for protein degradation. Ablation of rad23 accelerates the destruction several disease-causing, aggregation prone mutated proteins and confers benefits in a variety of model systems. Mammals have 2 rad23 isoforms, rad23A and rad23B. The objective of this proposal is to use genetic approaches and antisense oligonucleotide (ASO) technology to reduce the abundance of rad23 in mouse models of Amyotrophic Lateral Sclerosis, ALS. We will use the Thy1-TDP-43 transgenic mouse (TAR4/4) created by the lab of Samir Kumar-Singh. We hypothesize that loss of rad23 will accelerate the destruction of misfolded TDP43, promote proteostasis and delay or arrest disease progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2022
- Accession Number
- AD1175572
Entities
People
- Robert Kalb
Organizations
- Northwestern University