The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. Mwk mice harbor a gain-of-function mutation (T635A) in the Trpc3 gene encoding the nonselective transient receptor potential cation channel, type C3 (TRPC3), resulting in altered TRPC3 channel gating. TRPC3 is highly expressed in Purkinje cells during the phase of dendritogenesis. Interestingly, growth and differentiation of Purkinje cell dendritic arbors are profoundly impaired in Mwk mice. Our findings define a previously unknown role for TRPC3 in both dendritic development and survival of Purkinje cells, and provide a unique mechanism underlying cerebellar ataxia.
Proc Natl Acad Sci U S A
6706 - 6711
Amino Acid Sequence, Animals, Cell Differentiation, Cerebellar Ataxia, Dendrites, Ion Channel Gating, Male, Mice, Mice, Inbred BALB C, Mice, Neurologic Mutants, Molecular Sequence Data, Motor Activity, Phosphorylation, Point Mutation, Purkinje Cells, TRPC Cation Channels