RNA toxicity and perturbation ofrRNA processing in spinocerebellar ataxia type 2

Abstract

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of a CAG repeat in Ataxin-2 (ATXN2) gene. The mutant ATXN2 protein with a polyglutamine tract is known to be toxic and contributes to the SCA2 pathogenesis. OBJECTIVE: Here we tested the hypothesis that the mutant ATXN2 transcript with an expanded CAG repeat (expATXN2) is also toxic and contributes to SCA2 pathogenesis. METHODS: The toxic effect of expATXN2 transcripts on SK-N-MC neuroblastoma cells and primary mouse cortical neurons was evaluated by caspase 3/7 activity and nuclear condensation assay, respectively. RNA immunoprecipitation assay was performed to identify RNA binding proteins (RBPs) that bind to expATXN2 RNA. Quantitative PCR was used to examine if rRNA processing is disrupted in SCA2 and Huntington disease (HD) human brain tissue. RESULTS: expATXN2 RNA induces neuronal cell death, and aberrantly interacts with RBPs involved in RNA metabolism. One of the RBPs, transducin beta-like protein 3 (TBL3), involved in rRNA processing, binds to both expATXN2 and expanded huntingtin (expHTT) RNA in vitro. rRNA processing is disrupted in both SCA2 and HD human brain tissue. CONCLUSION: These findings provide the first evidence of a contributory role of expATXN2 transcripts in SCA2 pathogenesis, and further support the role expHTT transcripts in HD pathogenesis. The disruption of rRNA processing, mediated by aberrant interaction of RBPs with expATXN2 and expHTT transcripts, suggest a point of convergence in the pathogeneses of repeat expansion diseases with potential therapeutic implications.

Repeat RNA Toxicity Drives Ribosomal RNA Processing Defects in SCA2

“…18,19 This study opens up lines of investigation into the possible role of ribosomal abnormalities in another neurodegenerative disorder. 20 Taken together, the report by Li et al, 9 along with their earlier finding of a toxic antisense ATXN2 transcript, presents evidence for combinatorial protein-RNA driven pathology in SCA2 (Fig. 1).…”

“…[3][4][5][6] SCA2 belongs to a growing class of nucleotide repeat expansion disorders arising from unstable repeats in the genome. 7,8 In this issue of Movement Disorders, Li et al 9 add to an expanding body of literature indicating that repeat expansion disorders are often characterized by plural molecular pathogenic mechanisms.…”

RNA Foci Formation in a Retinal Glial Model for Spinocerebellar Ataxia Type 7

“…RNA-mediated toxicity may arise from aberrant interactions between mutant RNA and its protein partners in specific cell compartments. Several studies have demonstrated that mutant CAG mRNAs sequester proteins, including MBNL1, SRSF6, U2AF65, and nucleolin, alter key cellular mechanisms including alternative splicing regulation, ribosomal RNA maturation, recruitment of translation factors, and deregulation of the microRNA machinery [ 22 , 61 , 62 , 63 ]. Undoubtedly, any alteration in the aforementioned processes could impact on Müller cells’ function.…”

“…Interestingly, mutant RNA aggregates have been detected in fibroblasts from patients with these polyQ disorders [ 20 ]. In SCA3, the expression of untranslated CAG repeats in Drosophila caused the loss of neuronal integrity in the nervous system and the eye [ 21 ], while in SCA2, the abnormal interactions between mutant CAG transcript and RNA binding proteins resulted in neurotoxicity and deregulation of ribosomal RNA maturation [ 22 ]. Finally, the HD mutant RNA was found to provoke either defective alternative splicing, deregulated microRNA (miRNA) expression, or altered translation [ 23 ].…”

The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease

“…It was suggested that the expanded ATXN2 transcript aberrantly interacts with the transducin β-like protein 3 (TBL3), an RBP that is required for rRNA processing. The consequent failure of rRNA maturation could prevent the assembly of ribosomal proteins into ribosomal ribonucleoprotein subunits, hence contributing to neuronal death [108].…”