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 polyglutamin e tract. Overexpression of mutant ataxin-1 in Purkinje cells of transgenic mice results in a progressive ataxia and Purkinje cell pathology that are v ery similar to those seen in SCA1 patients. Two prominent aspects of pathol ogy in the SCA1 mice are the presence of cytoplasmic vacuoles and dendritic atrophy. We found that the vacuoles; in Purkinje cells seem to originate a s large invaginations of the outer cell membrane. The cytoplasmic vacuoles; contained proteins from the somatodendritic membrane, Including mGluR1, Gl uR Delta1/Delta2, GluR2/3, and protein kinase C (PKC) gamma. Further examin ation of PKC gamma revealed that its sequestration into cytoplasmic vacuole s was accompanied by concurrent loss of PKC gamma localization at the Purki nje cell dendritic membrane and decreased detection of PKC gamma by Western blot analysis. In addition, the vacuoles were immunoreactive for component s 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 an d loss of proteins including PKC gamma, are a part of the neuronal dysfunct ion in SCA1 transgenic mice.