Research Grant Award

Parminder J. S. Vig, Ph.D.

University of Mississippi Medical Center, Jackson, MS
Role of Bergmann glia in Purkinje cell development and pathology in SCA1

Spinocerebellar ataxia 1 (SCA1) is a dominantly inherited disease caused by the abnormal functions of ataxin-1 protein. SCA1 is associated with progressive ataxia resulting from the loss of cerebellar Purkinje cells and neurons in the brainstem. A prominent feature of SCA1 pathology is the presence of cytoplasmic vacuoles in Purkinje cells. In SCA1 mice, these vacuoles start appearing early on before the onset of ataxia. It is not understood why vacuoles are formed, however, they may have a role in Purkinje cell pathology. Our recent data show that the process of vacuolar formation is associated with degenerative changes in Purkinje cells. In addition, these vacuoles contain neighboring Bergmann glial specific proteins and are present both in transgenic mice and human patients with SCA1. Bergmann glial cells locate their cell bodies around Purkinje cells, and help Purkinje cell processes to grow and develop. We believe that early and continuous expression of mutant ataxin-1 in Purkinje cells compromises normal signal transduction mechanisms by impairing Purkinje cell. Bergmann glial crosstalk. This leads to vacuole formation and Purkinje cell death in SCA1. Therefore, to understand both the role of Bergmann glia in SCA1 pathogenesis and the functional relevance of the presence of glial-derived vacuoles, we will study developmental changes in different kinds of transgenic and wiltype mice. Using cell culture, it will be assessed if an interaction between Bergmann glia and Purkinje cells is required for vacuole formation. Purkinje and Bergmann glial cell cultures will be prepared from 0-1 day old mouse pups. To determine if glial protein S100B targets are affected in SCA1 Purkinje cells, S100B inhibitor will be intranasally administered to SCA1 mice to see if this treatment suppresses vacuole formation and SCA1 pathology. The significance of the present study is that an early identification of abnormal communication pathways between Bergmann glia and Purkinje cells could be targets of potential therapies for pre-symptomatic patients with SCA1. The long-term objective of this project is to understand neuron-glial relationship in neuronal degeneration in order to design therapeutic approaches in clinical management of SCA1 or other cerebellar ataxias.