Altered trafficking of membrane proteins in Purkinje cells of SCA1 transgenic mice

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expression of mutant ataxin-1 that contains an expanded polyglutamine tract. Overexpression of mutant ataxin-1 in Purkinje cells of transgenic mice results in a progressive ataxia and Purkinje cell pathology that are very similar to those seen in SCA1 patients. Two prominent aspects of pathology in the SCA1 mice are the presence of cytoplasmic vacuoles and dendritic atrophy. We found that the vacuoles; in Purkinje cells seem to originate as large invaginations of the outer cell membrane. The cytoplasmic vacuoles; contained proteins from the somatodendritic membrane, Including mGluR1, GluR Delta1/Delta2, GluR2/3, and protein kinase C (PKC) gamma. Further examination of PKC gamma revealed that its sequestration into cytoplasmic vacuoles was accompanied by concurrent loss of PKC gamma localization at the Purkinje cell dendritic membrane and decreased detection of PKC gamma by Western blot analysis. In addition, the vacuoles were immunoreactive for components of the ubiquitin/proteasome degradative pathway. These findings present a link between vacuole formation and loss of dendrites in Purkinje cells of SCA1 mice and Indicate that altered somatodendritic membrane trafficking and loss of proteins including PKC gamma, are a part of the neuronal dysfunction in SCA1 transgenic mice.