Abstract
Microsatellite expansions cause a number of dominantly-inherited neurological diseases. Expansions in coding-regions cause protein gain-of-function effects, while non-coding expansions produce toxic RNAs that alter RNA splicing activities of MBNL and CELF proteins. Bi-directional expression of the spinocerebellar ataxia type 8 (SCA8) CTG CAG expansion produces CUG expansion RNAs (CUGexp) from the ATXN8OS gene and a nearly pure polyglutamine expansion protein encoded by ATXN8 CAGexp transcripts expressed in the opposite direction. Here, we present three lines of evidence that RNA gain-of-function plays a significant role in SCA8: 1) CUGexp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons in the brain; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUGexp transcripts trigger splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 (GAT4/Gabt4). In vivo optical imaging studies in SCA8 mice confirm that Gabt4 upregulation is associated with the predicted loss of GABAergic inhibition within the granular cell layer. These data demonstrate that CUGexp transcripts dysregulate MBNL/CELF regulated pathways in the brain and provide mechanistic insight into the CNS effects of other CUGexp disorders. Moreover, our demonstration that relatively short CUGexp transcripts cause RNA gain-of-function effects and the growing number of antisense transcripts recently reported in mammalian genomes suggest unrecognized toxic RNAs contribute to the pathophysiology of polyglutamine CAG CTG disorders.
Highlights
Spinocerebellar ataxia type 8 (SCA8), is a slowly progressive neurodegenerative disease caused by a CTGNCAG expansion that primarily affects the cerebellum [1,2]
We describe several lines of evidence that RNA gain-offunction effects play a significant role in spinocerebellar ataxia type 8 (SCA8) and has broader implications for understanding the CNS effects of other trinucleotide expansion disorders including myotonic dystrophy type 1, Huntington disease like-2, and spinocerebellar ataxia type 7
We present three lines of evidence that CUG expansion (CUGexp) transcripts play a significant role in SCA8: 1) CUGexp transcripts accumulate as ribonuclear inclusions that colocalize with MBNL1 in selected neurons; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUGexp transcripts trigger alternative splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 (GAT4/Gabt4) which is associated with the predicted loss of GABAergic inhibition within the granular cell layer in SCA8 mice
Summary
Spinocerebellar ataxia type 8 (SCA8), is a slowly progressive neurodegenerative disease caused by a CTGNCAG expansion that primarily affects the cerebellum [1,2]. SCA8 patients and BAC-EXP mice were found to have 1C2-positive intranuclear inclusions in Purkinje cells and brainstem neurons that result from the expression of a nearly pure polyglutamine protein (ataxin 8) from a novel gene spanning the repeat in the opposite CAG direction (ATXN8). The expression of CUGexp transcripts from ATXN8OS in addition to CAGexp transcripts and a polyglutamine protein from ATXN8 suggests that SCA8 involves toxic gain-of-function effects at both the RNA (CUGexp) and protein (PolyQ) levels. An alternative hypothesis is that the SCA8 expansion affects the expression of an overlapping gene, KLHL1 and Klhl knockout mice have a subtle phenotype, the relevance of this model to the human disease is unclear [4]. CUGexp or CCUGexp transcripts accumulate as ribonuclear inclusions in DM1 and DM2 patient skeletal muscle [9,10,11] and alter the localization or regulation of RNA binding proteins CUGBP1
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