The heterogeneous nature of the genetic causes of ataxias and related disorders severely impedes the advancement of specific cures. Since genetically classified ataxia subtypes are often indistinguishable by clinical diagnosis, common pathological pathways are likely at play, and understanding the shared underlying mechanisms is a crucial direction of research. We have identified a novel mechanism of combinatorial post-transcriptional regulation between two disparate genes implicated in ataxia, PUM1 and VLDLR, and propose to investigate its role in a mouse model. Both PUM1 and VLDLR mutations have been independently found to cause cerebellar ataxia. Preliminary data shows that PUM can regulate the VLDLR 3' UTR through co-regulation with miRNAs. Therefore, elucidating the mechanistic connections between these ataxia- related genes promises to provide a more coherent view of disease development, to pinpoint key targets for therapeutic intervention, and to suggest methods of their control. The conceptual innovation of the proposed work resides in investigating a novel paradigm of combinatorial post-transcriptional control between RBPs and miRNAs, and its dysregulation, in mediating cerebellar ataxia. Furthermore, the study is significant because it aims to uncover new mechanistic insight into the connections between very recently identified factors in the disease. Achieving the specific aims of this proposal will provide a solid foundation for further major proposals studying the mechanism of PUM1 / miRNA interaction on the VLDLR mRNA and the means of its modulation.