Research Grant Award

Michael D Koob, PhD

University of Minnesota
Molecular Characterization of Purkinje cell function in mice carrying deletions of the SCA 8 ataxia locus

Spinocerebellar ataxia type 8 (SCA8) is an inherited neurodegenerative disease caused by a mutation in the DNA of SCA8 patients, but the precise relationship between this mutation and ataxia is complex and poorly understood. We have shown that the protein made from the gene that is closest to the SCA8 mutation, which is called the KLHL1 gene, is only present in cells in the brain. In order to determine what function this protein has in these cells, we engineered mice in which we removed this gene. We found that removing only one of the two copies of this gene normally present in mice causes these mice to walk in an abnormal way, to progressively lose coordination, and to have significant deficits in the part of their brain that typically degenerates in ataxia patients (i.e., the cerebellum). We also engineered mice in which we removed this gene only in a critically important type of cell in the cerebellum (i.e., Purkinje cells). These mice have all of the same abnormalities as the mice in which we deleted the gene in all of the cells in their body. This tells us that the most important functions of the Klhl1 protein with regards to maintaining normal movement coordination are in these Purkinje cells in the cerebellum. We predict from our experiments that the mutation that causes SCA8 ataxia in humans may be working through a mechanism involving the loss of KLHL1 activity in Purkinje cells, and that loss of proper expression from even one of the two copies of the KLHL1 gene would be sufficient to cause disease. This study will allow us to continue to define the precise molecular function of the Klhl1 protein in Purkinje cells through appropriate collaborative studies of the mice in which Klhl1 is removed and by identifying additional binding interactions of this protein.