%0 Journal Article %T Functional Annotation of Small Noncoding RNAs Target Genes Provides Evidence for a Deregulated Ubiquitin-Proteasome Pathway in Spinocerebellar Ataxia Type 1 %A Stephan Persengiev %A Ivanela Kondova %A Ronald E. Bontrop %J Journal of Nucleic Acids %D 2012 %I Hindawi Publishing Corporation %R 10.1155/2012/672536 %X Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by the expansion of CAG repeats in the ataxin 1 (ATXN1) gene. In affected cerebellar neurons of patients, mutant ATXN1 accumulates in ubiquitin-positive nuclear inclusions, indicating that protein misfolding is involved in SCA1 pathogenesis. In this study, we functionally annotated the target genes of the small noncoding RNAs (ncRNAs) that were selectively activated in the affected brain compartments. The primary targets of these RNAs, which exhibited a significant enrichment in the cerebellum and cortex of SCA1 patients, were members of the ubiquitin-proteasome system. Thus, we identified and functionally annotated a plausible regulatory pathway that may serve as a potential target to modulate the outcome of neurodegenerative diseases. 1. Introduction Aging is accompanied by cognitive decline in a major part of the population and is the primary risk factor for a number of neurodegenerative disorders. Aging-related neurodegenerative disorders are the culmination of many different genetic and environmental influences ultimately leading to the degeneration of specific neurons. The regulatory mechanisms controlling the expression of a number of genes may be altered during the course of certain neurodegenerative disorders, and recent evidence has indicated that small non-coding RNAs (snRNAs) and miRNAs might be a significant risk factor in neurodegeneration, including Alzheimer¡¯s and Parkinson¡¯s disease, spinocerebellar ataxia type 1 (SCA1), and triplet repeat disorders [1, 2]. A critical process in the development SCA1 is the deregulation of genes that affect neuronal cell survival mechanisms. In the case of SCA1 the expansion of the glutamine-rich region of ataxin-1 results in the accumulation of insoluble protein aggregates that are the main cause for the disease symptoms [3]. This view has recently been challenged by findings that, for some of these diseases, neurological symptoms begin appearing before protein aggregates form, or even when aggregates do not form at all [4]. These findings have led to the conclusion that accumulation of mutant ataxin-1 may be facilitated by the activation or deactivation of selective cell survival mechanism in the vulnerable neurons. Identifying the regulatory circuitry processes that control cell differentiation and transmission of information between neurons is fundamental to understanding changes in the aging brain. miRNAs regulate expression of protein-coding genes [5, 6]. Several lines of evidence indicate that miRNAs contribute to the %U http://www.hindawi.com/journals/jna/2012/672536/