Developing Tools to Probe DnaJB6 Dynamics in Spinobulbular Muscular Atrophy

PROJECT SUMMARY/ABSTRACT Spinobulbar Muscular Atrophy (SBMA) is an incurable neurodegenerative disorder that is characterized by the toxic accumulation of mutated androgen receptor (polyQ-AR) proteins. The molecular chaperone protein DnaJB6 is specialized to prevent polyQ-AR aggregation in cells and suppress disease phenotypes by preventing polyQ-AR aggregation and recruiting another chaperone protein, Hsp70 to polyQ-AR. While DnaJB6 represents an exciting target for developing SBMA chemotherapeutics, its dynamic protein-protein interactions and complex structure present significant challenges for efforts to discover and design DnaJB6 chemical ligands. DnaJB6 associates with itself to form complexes that appear to exchange between larger and smaller oligomeric states over time. I hypothesize that binding to either polyQ-AR or Hsp70 causes changes in the stability of DnaJB6 complexes, and that these changes in DnaJB6 dynamics can be exploited to discover chemical probes. DnaJB6 chemical probes could then be used to probe pathological aggregation in SBMA. To test this hypothesis, I will characterize DnaJB6 complex stability and discover chemical matter that tunes DnaJB6 activity in the K99 phase of this award. In the R00 phase, I will use these molecules to probe SBMA in cell and animal models. This work is significant because the tools resulting from my studies will not only have applicability for studying SBMA, but also for other neurodegenerative disease where DnaJB6 can suppress protein aggregation (i.e. Huntington's Disease, Spinocerebellar Ataxias, and Parkinson's Disease) and chaperone biology more broadly. My proposed studies are innovative, as they will yield the first DnaJB6-targeted chemical probes and a novel strategy to understand the molecular underpinnings of SBMA.