Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by an expansion of a polyglutamine tract in ataxin-1. Protein misfolding and decreased clearance of the mutant protein are early events in SCA1, however ataxin-1 's function is unknown. Various observations strongly suggest a role of ataxin-1 in RN A processing pathways. Ataxin-1 can bind RNA in vitro, and two related genes, mushroom body expressed (mub) and pasilla (ps), which encode KH-type RNA binding proteins, are potent modifiers of neurodegeneration of a Drosophila model of SCA1. Loss of function of Nova proteins, mammalian homologues of mub and ps, cause SCA1-like phenotypes in humans and mice. More recently, protein-protein interaction studies in our lab identified a network of RNA-binding proteins and splicing factors as direct interactors of ataxin-1. We propose that ataxin-1 plays a role in RNA metabolism, and that changes in RNA splicing might be at the core of SCA1 pathogenesis. To determine if Nova modifies SCA1 pathogenesis, I mated SCA1 mouse models with mice heterozygous for Nova-1 and Nova-2 loss of function alleles. At a functional level, splicing assays will determine if mutant ataxin-1 alters Nova-dependent splicing. Additionally, I will identify RNA splicing changes in SCA1 in vivo, using a splicing microarray approach. Finally, I will study the expression of validated RNA-binding protein interactors of ataxin-1 in the brain to identify relevant interactions to SCA1 pathogenesis. Taken together, these studies will provide insight into ataxin-1's function in RNA metabolism, and the relevance of RNA misregulation in SCA1 pathogenesis. ? ? ?
| Crespo-Barreto, Juan; Fryer, John D; Shaw, Chad A et al. (2010) Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis. PLoS Genet 6:e1001021 |
