Targeting Protein Quality Control Pathways in Spinal and Bulbar Muscular Atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a progressive neurodegenerative disease caused by a CAG/glutamine (polyQ) expansion in the androgen receptor (AR). Like many other age-dependent neurodegenerative diseases, SBMA is characterized by the buildup of misfolded proteins into nuclear aggregates and neurodegeneration. The mutant protein disrupts several cellular pathways, and decreasing levels of disease causing protein may circumvent several of the downstream pathological processes. Here we investigate the effects of manipulating protein quality control pathways in cell and animal models of SBMA, identifying novel therapeutic targets and advancing our understanding of molecular chaperones and their role in protein triage. Cells degrade proteins through two main pathways, autophagy and the ubiquitin proteasome pathway. Autophagy degrades cytosolic proteins in bulk, and increased autophagy has been shown to be beneficial in some models of protein aggregation diseases. Our results however, show that activating autophagy increases muscle wasting, while inhibiting autophagy significantly increases the lifespan and size of muscle fibers in a mouse model of SBMA. Our findings are surprising, and suggest that activation of autophagy in SBMA may exacerbate disease progression. The Hsp90/Hsp70-based chaperone machinery regulates the stabilization and degradation of Hsp90 clients through the proteasome, and presents an alternative therapeutic target to modulate proteostasis. Little is known however, about how this machinery functions to triage misfolded proteins, and few modulators of Hsp70 exist. Here we advance our understanding of chaperone machinery function, and present novel strategies to target Hsp70’s substrate affinity. We demonstrate that inhibiting Hsp70 function leads to accumulation of toxic AR, while increasing Hsp70 substrate affinity through overexpression of the co-chaperone Hip, or through treatment with a newly identified small molecule allosteric activator, promotes client protein ubiquitination and polyQ AR clearance. Both genetic and pharmacologic approaches to increase Hsp70 activity rescue disease phenotype in a Drosophila model of SBMA. Our results reveal a new therapeutic strategy of targeting Hsp70 to treat SBMA and perhaps other neurodegenerative diseases, while providing insights into the role of the chaperone machinery in protein quality control.PhDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91413/1/amwang_1.pd