Neurodegenerative disorders associated with protein aggregation include nine untreatable diseases caused by CAG/glutamine tract (polyQ) expansions. One of these disorders, spinobulbar muscular atrophy (SBMA), is characterized by degeneration of lower motor neurons and is caused by a mutation in the androgen receptor (AR) gene. The mutant protein undergoes hormone-dependent nuclear translocation, unfolding and oligomerization, steps that are critical to toxicity and to the development of progressive proximal limb and bulbar muscle weakness in men. Although the disease causing mutation was identified two decades ago, treatments available to SBMA patients remain largely supportive. Furthermore, the cellular pathways that degrade the mutant protein remain 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 the Hsp90-based chaperone machinery in the protein quality control decisions that govern polyQ AR degradation. Our central hypothesis is that Hsp70 and Hsp90 have essentially opposing roles in the triage of the polyQ AR, in that Hsp70 promotes substrate ubiquitination whereas Hsp90 inhibits ubiquitination. 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. Here we will use genetic and pharmacological tools to define the consequences of allosterically activating Hsp70-dependent ubiquitination. Additionally, as our data point to contributions from both skeletal muscle and motor neurons to the disease phenotype, we will use genetic approaches to determine the extent to which toxicity at each site must be targeted to achieve beneficial therapeutic effects. The rationale of the proposed work is that establishing the mechanisms that regulate polyQ AR degradation will identify targets that can be exploited by the development of new therapies. Genetic and biochemical approaches will be used to determine the extent to which allosteric activators of Hsp70 promote clearance of the polyQ AR (Aim 1), to identify critical sties of polyQ AR toxicity in SBMA mice (Aim 2), and to establish the effects of novel, small molecule allosteric activators of Hsp70 in SBMA mice (Aim 3). These studies are expected to have a significant positive impact by defining pathways that limit SBMA toxicity while providing proof-of-concept data supporting a new therapeutic approach. As Hsp70 also regulates quality control decisions governing the turnover of other mutant proteins that cause neurodegeneration, we expect that the approaches defined here will inform therapeutic strategies that will be broadly applicable.

Public Health Relevance

of the proposed studies to public health is that they will define allosteric activation of Hsp70 as a strategy to promote degradation of the polyQ AR, the mutant protein that causes SBMA. This work will characterize both genetic and pharmacological Hsp70 activators, with the expectation that they will ameliorate the SBMA phenotype in model systems and speed the advance toward disease-modifying therapies.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Chua, Jason P; Reddy, Satya L; Merry, Diane E et al. (2014) Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy. Hum Mol Genet 23:1376-86
Lieberman, Andrew P; Yu, Zhigang; Murray, Sue et al. (2014) Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy. Cell Rep 7:774-84
Wang, Adrienne M; Miyata, Yoshinari; Klinedinst, Susan et al. (2013) Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol 9:112-8
Yu, Zhigang; Wang, Adrienne M; Adachi, Hiroaki et al. (2011) Macroautophagy is regulated by the UPR-mediator CHOP and accentuates the phenotype of SBMA mice. PLoS Genet 7:e1002321
Mo, Kaiguo; Razak, Zak; Rao, Pengcheng et al. (2010) Microarray analysis of gene expression by skeletal muscle of three mouse models of Kennedy disease/spinal bulbar muscular atrophy. PLoS One 5:e12922
Johansen, Jamie A; Yu, Zhigang; Mo, Kaiguo et al. (2009) Recovery of function in a myogenic mouse model of spinal bulbar muscular atrophy. Neurobiol Dis 34:113-20
Yu, Zhigang; Wang, Adrienne M; Robins, Diane M et al. (2009) Altered RNA splicing contributes to skeletal muscle pathology in Kennedy disease knock-in mice. Dis Model Mech 2:500-7
Lieberman, Andrew P; Robins, Diane M (2008) The androgen receptor's CAG/glutamine tract in mouse models of neurological disease and cancer. J Alzheimers Dis 14:247-55