Development of therapeutics for SCA48

Abstract C-terminus of HSC70 Interacting Protein (CHIP) is a neuroprotective protein that is beneficial in many different neurodegenerative diseases. More recently mutations in CHIP have been identified as the cause of two neurodegenerative diseases. Recessive mutations in CHIP cause Spinocerebellar ataxia autosomal recessive type 16 (SCAR16), while dominant mutations cause Spinocerebellar ataxia type 48 (SCA48). While SCAR16 is a very rare disease, SCA48 is a more common form of ataxia. Many mutations that cause SCA48 exist in the tetratricopeptide repeat domain of CHIP and map to a single interface between the first and second TPR repeat of CHIP. That led us to investigate the importance of this domain. Our findings indicate that mutations in this domain cause SCA48 by inducing a structural change that partially unfolds the TPR domain of CHIP. Importantly this unfolding event can be reversed by addition of excess ligand suggesting that mutations that cause SCA48 do not terminally unfold the TPR domain of CHIP. Importantly these results also suggest that one could identify small molecules that stabilize this domain and thus may be therapeutic for patients with SCA48. Here we propose to optimize and miniaturize a series of assays. These assays will then be utilized to screen for small molecules that restore the proper fold and function to the TPR domain of CHIP. Compounds from the screen will then be evaluated with secondary and tertiary assays to identify hits. These hits will then be tested in cell culture models of SCA48 to see if they reverse disease phenotypes. Together the work proposed in this application will put us on the road to developing small molecules that may one day be therapeutically useful.