Neurodevelopmental deficits as a therapeutic target for adult-onset Spinocerebellar Ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is a late onset cerebellar neurodegenerative disorder caused by the mutation (abnormal polyglutamine expansion) in Ataxin-1 gene. The mutant protein is especially toxic to Purkinje cells in the cerebellum that are crucial for regulating movement execution in mammals. It is puzzling that symptoms do not appear until later in life when the mutant protein is being expressed since before birth. However, the biological changes at the molecular level occur within the first few weeks after birth in mouse models. We are particularly intrigued by these early molecular changes and started looking closely for changes that occur at a cellular level in cerebellum during early developmental stage and we found the remarkable changes in function of cerebellar stem cells. We discovered that with SCA1, the cerebellum produce high number of stem cells during development which in turn gives rise to enhanced number of inhibitory neurons (Inhibit the activity of neighboring neurons) and fewer glial cells (support and maintain environment to the neurons). Furthermore, the elevated number inhibitory neurons show the toxic effect on neighboring Purkinje cells. In this proposal, we aim to target these early developmental changes where we relieve exaggerated GABAergic inhibition using drug model thus can be used as a potential therapeutic target for SCA1 disease.