An Antisense CAG Repeat Transcript at JPH3 Locus Mediates Expanded Polyglutamine Protein Toxicity in Huntington's Disease-like 2 Mice

Wilburn, Brian; Rudnicki, Dobrila D.; Zhao, Jing; Weitz, Tara M.; Yin, Cheng; Gu, Xiaofeng; Greiner, Erin R.; Park, Chang Sin; Wang, Nan; Sopher, Bryce L.; Spada, Albert R. La; Osmand, Alex; Margolis, Russell L.; Sun, Yi; Yang, X. William

doi:10.1016/j.neuron.2011.03.021

Cited by 122 publications

(118 citation statements)

References 40 publications

(88 reference statements)

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“…Interestingly, the soluble form of mutant Htt also promoted the degradation of CBP [84]. In addition, CBP sequestration into ubiquitin-positive nuclear inclusions and decreased CBP-mediated activation of gene expression [e.g., brain-derived neurotrophic factor (Bdnf)] were shown in a newly generated mouse model displaying HD-like-2, consistent with observations in HD patient brains [85]. In Drosophila models, reduced PCAF levels were associated with enhanced neurodegeneration.…”

Section: Hat Impairment In Neurodegenerative Disorderssupporting

confidence: 79%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Section: Hat Impairment In Neurodegenerative Disorderssupporting

confidence: 79%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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“…Although in most repeat expansion diseases, the sense strand transcript or its translated protein products are thought to have primacy in disease pathogenesis, discovery of antisense strand transcripts is leading to increasing appreciation of their potential significance in disease pathogenesis (45)(46)(47)(48)(49)(50)(51)56). In FXTAS, antisense strand transcripts, as well as sense strand transcripts, are up-regulated, polyadenylated at the 3′ end, and capped at the 5′ end (47), although only the sense strand is known to generate nuclear inclusions (57).…”

Section: Discussionmentioning

confidence: 99%

“…Recognizing that in several other examples of expanded nucleotide repeat diseases, bidirectional transcription of the repeat has been identified (45)(46)(47)(48)(49)(50)(51), and that a recent study reported antisense transcripts in C9orf72 patient nervous systems (20), we examined C9orf72 patient fibroblasts for accumulation of RNAs transcribed in the antisense direction. Using FISH with LNA probes to the antisense strand of the hexanucleotide repeat GGCCCC, RNA foci were identified in all six fibroblasts from C9orf72 expansion patients tested and were not observed in fibroblasts from three nonaffected individuals (Fig.…”

Section: Antisense Strand Of C9orf72 Is Transcribed and Ggcccc Expanmentioning

confidence: 99%

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

Lagier‐Tourenne

Baughn

Rigo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.E xpanded hexanucleotide repeats in the first intron of the chromosome 9 open reading frame 72 (C9orf72) gene were recently identified (1, 2) as the most common genetic cause of ALS, frontotemporal degeneration (FTD), or concomitant ALS/ FTD (3, 4). The mechanisms by which the expanded repeats cause neurodegeneration are unknown, but leading candidate mechanisms are RNA-mediated toxicity, loss of the C9orf72 gene function (from reduced C9orf72 produced by the allele with the expansion), or a combination of the two.RNA-mediated toxicity from nucleotide repeat expansion was initially described for CUG expansion in the RNA encoded by the DMPK gene in myotonic muscular dystrophy (5). A consensus view is that RNA toxicity plays a crucial role in a variety of repeat expansion disorders (6). A hallmark of these disorders is the accumulation of expanded transcripts into nuclear RNA foci (7). RNAs harboring a long stretch of repeats are thought to fold into stable structures and sequester RNA binding proteins, which, in turn, sets off a molecular cascade leading to neurodegeneration (7). In myotonic dystrophy, sequestration and functional disruption of the muscleblind-like family of RNA binding proteins are associated with specific splicing and expression changes in affected tissues (5,(8)(9)(10)(11)(12).Sequestration of one or more RNA binding proteins into pathological RNA foci has ...

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“…It has become clear that antisense transcripts are involved in triplet repeat disorders and bidirectional transcription has thus far been identified in DM1, spinocerebellar ataxia 8 (SCA8), and HD like 2 (HDL2) (Moseley et al, 2006;Wilburn et al, 2011).…”

Section: Htt Antisense Transcriptionmentioning

confidence: 99%

“…A novel transcript called ataxin-8, which encodes a polyQ protein, was expressed from the opposite strand, suggesting polyQ induced toxicity (Moseley et al, 2006). A BAC HDL2 mouse model with a pathogenic CTG repeat on the sense and expanded CAG repeat on the antisense strand at the Junctophilin-3 locus showed both RNA toxicity caused by its expanded CUG repeat as well as protein toxicity by its polyQ translated expanded CAG repeat (Wilburn et al, 2011). These findings suggest that triplet repeat disorders can involve toxic gain of function of both protein and RNA by bidirectional transcription.…”

Section: Htt Antisense Transcriptionmentioning

confidence: 99%