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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for amyotrophic lateral sclerosis and frontotemporal dementia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Gene Yeo

PROVIDER: E-GEOD-51741 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Lagier-Tourenne Clotilde C Baughn Michael M Rigo Frank F Sun Shuying S Liu Patrick P Li Hai-Ri HR Jiang Jie J Watt Andrew T AT Chun Seung S Katz Melanie M Qiu Jinsong J Sun Ying Y Ling Shuo-Chien SC Zhu Qiang Q Polymenidou Magdalini M Drenner Kevin K Artates Jonathan W JW McAlonis-Downes Melissa M Markmiller Sebastian S Hutt Kasey R KR Pizzo Donald P DP Cady Janet J Harms Matthew B MB Baloh Robert H RH Vandenberg Scott R SR Yeo Gene W GW Fu Xiang-Dong XD Bennett C Frank CF Cleveland Don W DW Ravits John J

Proceedings of the National Academy of Sciences of the United States of America 20131029 47

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 ...[more]

PMID: 24170860

Similar Datasets

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for amyotrophic lateral sclerosis and frontotemporal dementia (Multiplex Analysis of PolyA-linked Sequences)

Project description:Purpose: The purpose of this experiment is to identify a C9-ALS/FTD specific genomic profile in fibroblast lines that is distinct from sporadic ALS without C9orf72 expansion and non-neurologic control cells. The study will then evaluate the effect on this identified profile of ASO treatment targeting the sense strand RNA transcript of the C9orf72 gene. Methods: Expression profiling was performed on RNAs from fibroblasts of four C9orf72 patients, four control individuals and four sporadic ALS patients using Multiplex Analysis of PolyA-linked Sequences method. Results: Hierarchical clustering of expression values for all genes showed that the four C9orf72 patient lines had an expression profile distinct from control and sporadic ALS lines. Statistical comparison of expression values between the four C9orf72 lines and the four control lines revealed that 122 genes were upregulated (defined by a False Discovery Rate FDR<0.05) and 34 genes were downregulated (defined by a False Discovery Rate FDR <0.05) in C9orf72 patient fibroblasts. Conclusions: A genome wide RNA signature can be defined in fibroblasts with C9orf72 expansion. ASO-mediated reduction of C9orf72 RNA levels in fibroblasts with the hexanucleotide expansion efficiently reduced accumulation of GGGGCC RNA foci. This did not, however, generate a reversal of the C9orf72 RNA profile. Use of Multiplex Analysis of PolyA-linked Sequences to identify expression changes in fibroblasts from amyotrophic lateral sclerosis and frontotemporal dementia patients harboring an hexanucleotide expansion in the C9orf72 gene.

2013-11-12 | E-GEOD-51684 | biostudies-arrayexpress

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for amyotrophic lateral sclerosis and frontotemporal dementia (strand specific RNA-seq)

Project description:Purpose: The purpose of this experiment is to identify expression changes after ASO-dependent depletion of mouse C9orf72 in the spinal cord of wild-type C57Bl/6 female mice. Methods: Strand specific RNA-seq was performed using RNAs extracted from spinal cord of C57Bl/6 mice two weeks after intracerebroventricular stereotactic injection of saline (n=3), a control ASO (n=3) or an ASO targeting mouse C9orf72 (n=3). C9orf72 RNA levels were reduced to approximately 30% of control levels in spinal cords from mice treated with the C9orf72 ASO. Results: Statistical comparison of RPKM values between RNAs from C9orf72 and control ASO treated animals or C9orf72 and saline treated samples revealed that only 12 genes were consistently upregulated (defined by P<0.05 adjusted for multiple testing) and 12 genes including C9orf72 were downregulated (defined by P<0.05 adjusted for multiple testing). Conclusions: Only few RNA expression changes were identified in the spinal cord following reduction of C9orf72. Use of strand specific RNA-seq to test the consequences of C9orf72 loss of function in mouse spinal cord.

2013-11-12 | E-GEOD-51685 | biostudies-arrayexpress