# Mechanisms of motor neuron toxicity in Kennedy disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $512,581

## Abstract

ABSTRACT
Spinal and bulbar muscular atrophy (SBMA) is a degenerative disorder of lower motor neurons and skeletal
muscle caused by a CAG/glutamine tract expansion in the androgen receptor (AR) gene. The polyglutamine
AR (polyQ AR) undergoes hormone-dependent nuclear translocation and unfolding, steps that are essential to
toxicity and to the development of progressive muscle weakness in men. Although the disease causing
mutation was identified over two and a half decades ago, only supportive therapies are currently available to
SBMA patients. Model systems that have been used to study disease pathogenesis show hormone and
glutamine length-dependent changes in an array of downstream pathways, supporting a role for divergent
mechanisms in toxicity. These observations prompted us to focus instead on understanding the proximal
mechanisms that regulate degradation of the mutant androgen receptor protein in hopes of harnessing these
for the discovery of effective treatments. However, these clearance pathways are incompletely defined, and
this lack of knowledge hinders the development of disease-modifying therapies. The objective of this
application is to define the role of Hsp70 in the protein quality control decisions that govern degradation of the
full-length polyQ AR. The scientific premise of this application is that the Hsp70, acting through the
Hsp90/Hsp70-based machinery and the Hsp70/Hsp110 disaggregase machinery, plays a critical role in
controlling polyQ AR degradation through the proteasome. This premise provides the foundation for our central
hypothesis that Hsp70 targeted strategies will promote ubiquitination and clearance of the mutant protein. This
hypothesis springs from our preliminary data showing that association with Hsp90 stabilizes the polyQ AR,
while unfolding of the mutant protein leads to ubiquitination by Hsp70-dependent E3 ligases. Moreover, we will
build upon our published studies demonstrating that allosteric regulation of Hsp70 to increase binding to
misfolded proteins enhances clearance of the polyQ AR in cells and alleviates toxicity in a Drosophila model.
The rationale of the proposed work is that establishing the mechanisms that regulate polyQ AR degradation
will identify targets that can be exploited for the development of new therapies. Structural, biochemical, genetic
and pharmacological approaches will be used to characterize the Hsp70-CHIP complex with the polyQ AR that
regulates protein triage (Aim 1), establish the effects of genetic and small molecule allosteric regulators of
Hsp70 in SBMA models (Aim 2), and determine effects of polyQ AR expression on ubiquitin-proteasome
pathway function (Aim 3). These studies are expected to characterize the structure and function of the cellular
machinery that regulates polyQ AR degradation and provide proof-of-concept data supporting a therapeutic
approach centered on targeting Hsp70. As this chaperone also regulates quality control decisions governing
the turnover of oth...

## Key facts

- **NIH application ID:** 10142545
- **Project number:** 5R01NS055746-15
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ANDREW P LIEBERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $512,581
- **Award type:** 5
- **Project period:** 2007-03-05 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142545

## Citation

> US National Institutes of Health, RePORTER application 10142545, Mechanisms of motor neuron toxicity in Kennedy disease (5R01NS055746-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142545. Licensed CC0.

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