# RAD23 Control of ALS phenotypes

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $398,750

## Abstract

Abstract
 The accumulation of damaged, misfolded and aggregation-prone proteins in
neurodegenerative diseases reflects corruption of cellular protein homeostasis (or
“proteostasis”). Proteostasis is the proper balance of protein synthesis and protein degradation
that is required for optimal cellular functioning. 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. A key protein in this process is RAD23. RAD23 promotes the
degradation of some proteins and stabilizes cellular levels of other proteins. The mechanism
underlying these diametrically opposed operations is not understood. Interestingly, ablation of
rad23 accelerates the destruction several disease-causing, aggregation-prone mutated proteins
(i.e., polyQ expanded Ataxin3, TDP43, SOD) and confers benefits in a variety of model
systems. We hypothesize that RAD23 bridges ubiquitinated misfolded proteins with the
proteasome and in doing so, sterically or allosterically inhibits proteasome function. In this way,
RAD23 impairs proteostasis. In specific aim #1, we will use imaging and biochemical
approaches to test this mechanism of RAD23 action. In in vitro and C.elegans models of ALS,
loss of RAD23 is health promoting – whether this is true in mouse models is unknown.
Mammals have 2 rad23 isoforms, rad23A and rad23B. In specific aims 2-4, we will use genetic
and anti-sense oligomer technology to ablate and/or knockdown rad23A, rad23B or both in
several mouse models of ALS. We will comprehensively interrogate the effects of loss of
rad23A/B on mouse survival, behavior and biochemistry. The successful completion of these
studies has the potential to be translated into clinical therapeutics.

## Key facts

- **NIH application ID:** 10274489
- **Project number:** 1R01NS122908-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Robert G Kalb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,750
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274489

## Citation

> US National Institutes of Health, RePORTER application 10274489, RAD23 Control of ALS phenotypes (1R01NS122908-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10274489. Licensed CC0.

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