Molecular chaperones, such as Hsp70 and Hsp90, may help protect against neurodegenerative disorders, such as Alzheimer's and Huntington's diseases, which are caused by aberrant protein misfolding. However, a dearth of small molecule partners for the chaperones have limited our ability to probe their function in models of these diseases. The long-term goal of the Gestwicki laboratory is to uncover inhibitors and agonists of the chaperones to open new opportunities for exploration in this area. The objective of this particular proposal is to identify and characterize agonists of Hsp70 and use these to study the role of this chaperone in polyglutamine expansion (polyQ) models of Huntington's disease. Our central hypothesis is that direct stimulation of Hsp70 will provide relief from polyQ misfolding. In preliminary studies, we have uncovered small molecules that promote Hsp70's function and protect yeast and mammalian cell models of disease. Moreover, we have used these chemical probes to implicate Hsp70 as a crucial mediator of aggregation. Guided by this strong preliminary evidence, we propose three specific aims: (1) Identify additional small molecules that modify Hsp70's chaperone activity (2) Explore the interaction between these compounds and Hsp70 (3) Use these chemical tools to investigate how Hsp70 protects against polyQ self-assembly. This approach is innovative because other strategies have relied on initiation of the global cellular stress responses to modulate Hsp70 function. In contrast, our approach directly targets the chaperone without perturbing other cellular processes. This is significant because our chemical probes might allow us to, for the first time, identify Hsp70 as a drug target for neurodegenerative disorders and learn more about its role in disease.

Public Health Relevance

Neurodegenerative disease is one of the greatest threats facing an aging population and the outlook for pharmaceutical intervention is uncertain. We have developed a new approach to discovery in this area by directly targeting molecular chaperones.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059690-03
Application #
7764643
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Sutherland, Margaret L
Project Start
2008-02-01
Project End
2013-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
3
Fiscal Year
2010
Total Cost
$316,607
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zuiderweg, Erik R P; Gestwicki, Jason E (2017) Backbone and methyl resonance assignments of the 42 kDa human Hsc70 nucleotide binding domain in the ADP state. Biomol NMR Assign 11:11-15
Rauch, Jennifer N; Tse, Eric; Freilich, Rebecca et al. (2017) BAG3 Is a Modular, Scaffolding Protein that physically Links Heat Shock Protein 70 (Hsp70) to the Small Heat Shock Proteins. J Mol Biol 429:128-141
Zuiderweg, Erik R P; Hightower, Lawrence E; Gestwicki, Jason E (2017) The remarkable multivalency of the Hsp70 chaperones. Cell Stress Chaperones 22:173-189
Rauch, Jennifer N; Olson, Steven H; Gestwicki, Jason E (2017) Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules. Cold Spring Harb Perspect Med 7:
Khachatoorian, Ronik; Riahi, Rana; Ganapathy, Ekambaram et al. (2016) Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly. Int J Antimicrob Agents 47:289-96
Young, Zapporah T; Rauch, Jennifer N; Assimon, Victoria A et al. (2016) Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy. Cell Chem Biol 23:992-1001
Rauch, Jennifer N; Zuiderweg, Erik R P; Gestwicki, Jason E (2016) Non-canonical Interactions between Heat Shock Cognate Protein 70 (Hsc70) and Bcl2-associated Anthanogene (BAG) Co-Chaperones Are Important for Client Release. J Biol Chem 291:19848-57
Martin, Mackenzie D; Baker, Jeremy D; Suntharalingam, Amirthaa et al. (2016) Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules. ACS Chem Biol 11:2041-8
Li, Xiaokai; Shao, Hao; Taylor, Isabelle R et al. (2016) Targeting Allosteric Control Mechanisms in Heat Shock Protein 70 (Hsp70). Curr Top Med Chem 16:2729-40
Gabai, Vladimir L; Yaglom, Julia A; Wang, Yongmei et al. (2016) Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells. Cancer Res 76:5926-5932

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