Differential roles of the mevalonate pathway in the development and survival of mouse Purkinje cells in culture

Abstract

The cerebellum is an important locus for motor learning and higher cognitive functions, and Purkinje cells constitute a key component of its circuit. Biochemically, significant turnover of cholesterol occurs in Purkinje cells, causing the activation of the mevalonate pathway. The mevalonate pathway has important roles in cell survival and development. In this study, we investigated the outcomes of mevalonate inhibition in immature and mature mouse cerebellar Purkinje cells in culture. Specifically, we found that the inhibition of the mevalonate pathway by mevastatin resulted in cell death, and geranylgeranylpyrophosphate (GGPP) supplementation significantly enhanced neuronal survival. The surviving immature Purkinje cells, however, exhibited dendritic developmental deficits. The morphology of mature cells was not affected. The inhibition of squalene synthase by zaragozic acid caused impaired dendritic development, similar to that seen in the GGPP-rescued Purkinje cells. Our results indicate GGPP is required for cell survival and squalene synthase for the cell development of Purkinje cells. Abnormalities in Purkinje cells are linked to motor-behavioral learning disorders such as cerebellar ataxia. Thus, serious caution should be taken when using drugs that inhibit geranylgeranylation or the squalene-cholesterol branch of the pathway in the developing stage.