Spinocerebellar Ataxia TYPE 2: Ataxin-2 mechanisms and boold biomarkers

Abstract

Spinocerebellar Ataxia Type 2 is an autosomal dominant movement disorder caused by trinucleotide expansions in the ATXN2 gene (>34 CAG repeats). Intermediate expansions of 26-39 repeats are considered as risk factors for several other neurodegenerative disorders, such as ALS, PD and HSP. Ataxin-2 localizes to the rough-ER, binds to the 3’-UTRs of mRNA molecules together with PABPC1 and modulates ribosomal translation. Under stress conditions, ataxin-2 controls the assembly of stress granules, where it sequesters mRNAs and vital proteins that regulate cellular growth and proliferation. Although ataxin-2 is known to contribute to many cellular processes, its exact function is not entirely understood. In order to elucidate ataxin-2 function and the expansion-related pathogenesis and to identify blood biomarkers of SCA2, the transcriptome profiles of Atxn2 knock-out mice and SCA2 patients from a large pedigree were examined. A cluster of genes, whose products are normally secreted to the extracellular fluids, emerged among the 100 most significantly downregulated genes in the mouse transcriptome data. Significant upregulations of Apo-AI, Hemopexin and SERPINA1 proteins were found in Atxn2-KO mouse liver. Candidate blood RNA biomarkers were inferred from the whole blood transcriptome data of SCA2 patients via either direct unbiased filtration or by focusing on neurodegeneration-associated genes. Independent validations of the candidate genes revealed significant upregulations in ETV7, SERINC2, and ATXN1, along with downregulations in DACT1, MATR3, and PHTF2 in patient blood. Gene Set Enrichment Analysis of the patient transcriptome data presented an enrichment in the Parkinson’s disease pathway, key components of which were further analyzed in the context of ATXN2 knock-down neuroblastoma cells. This thesis exhibits insights into the native function and expansion-induced pathogenesis of ataxin-2 by investigating the downstream effects of ATXN2 deficiency and expansions on global and gene-specific transcription profiles.