NAF Ataxia Research Studies Currently Underway

Pawel Kermer, MD

University of Goettingen
Function of the multifunctional protein BAG! In SCA-3 pathology

Summary: Worldwide, SCA affects some 0.9-3/100,000 individuals, of which SCA-3 is the most common dominantly inherited ataxia. Treatment of the disease is still symptomatic. Today, neuronal degeneration in the basal ganglia, the brain stem and the cerebellum leading to physical/mental disability and death within years can not be prevented or stopped. Thus, we are in great need for therapeutic strategies aiming at blocking continuous pathology in SCA. In the present proposal, we suggest experiments involving the neuroprotective protein BAG1 which has been characterized as multifunctional protein linking cell cycle, cell death and stress responses. With its neuroprotective activity being linked to increased levels and foldase activity of Hsp70, BAG1 is a highly interesting gene to study in the context of SCA-3 pathology. Identification of BAG1 as neuroprotectant in SCA as well as identifying the potential underlying mechanisms could have clinical implications, since the 3-dimensional structure of the BAG1/Hsp70-ATPase domain complex has been solved, and critical contact sites have been mapped for BAG1 binding and co-chaperone activity. Thus, it is conceivable that small-molecule drugs could be identified or synthesized for neuroprotection that occupy the BAG1-binding site on the ATPase domain of Hsp70/Hsc70, acting as BAG1 mimics, and thereby enhancing Hsp70/Hsc70 function.