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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptome profile of C9ORF72 ALS fibroblast

ABSTRACT: The purpose of this experiment was to compare the differences in transcript levels between RNA samples collected from fibroblasts from healthy control patients, amyotrophic lateral sclerosis (ALS) patients carrying an expanded GGGGCC repeat mutation in the chromosome 9 open reading frame 72 gene and ALS patients with a mutation in the SOD1 gene.

ORGANISM(S): Homo sapiens

SUBMITTER: Christopher Donnelly

PROVIDER: E-MTAB-1926 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention.

Donnelly Christopher J CJ Zhang Ping-Wu PW Pham Jacqueline T JT Haeusler Aaron R AR Mistry Nipun A NA Vidensky Svetlana S Daley Elizabeth L EL Poth Erin M EM Hoover Benjamin B Fines Daniel M DM Maragakis Nicholas N Tienari Pentti J PJ Petrucelli Leonard L Traynor Bryan J BJ Wang Jiou J Rigo Frank F Bennett C Frank CF Blackshaw Seth S Sattler Rita R Rothstein Jeffrey D JD

Neuron 20131001 2

A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCCexp RNA foci, (2) dysregul ...[more]

PMID: 24139042

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Transcription profiling by array of post-mortem brain cortex from healthy control patients and amyotrophic lateral sclerosis patients that carry an expanded GGGGCC repeat mutation in the chromosome 9 open reading frame 72 (C9ORF72) gene

Project description:The purpose of this experiment was to compare differences in the transcript level between RNA samples collected from post-mortem motor cortex from healthy control patients and amyotrophic lateral sclerosis (ALS) patients that carry an expanded GGGGCC repeat mutation in the chromosome 9 open reading frame 72 (C9ORF72) gene.

2013-10-29 | E-MTAB-1925 | biostudies-arrayexpress

Wide-ranging analysis of microRNA profiles in sporadic amyotrophic lateral sclerosis using next-generation sequencing

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2018-12-12 | E-MTAB-7073 | biostudies-arrayexpress

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Differences between C9ORF72 iPS neuronal and Control and SOD1D90A iPS neuronal transcriptomes

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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

iPSC derived motor neuron cultures from C9ORF72 carriers

Project description:Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat–containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-?, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS. Transcriptome profiling from iPSC derived motor neurons compared to controls

2013-11-07 | E-GEOD-52202 | biostudies-arrayexpress

C9ORF72 GGGGCC expanded repeats produce splicing dysregulation which correlates with disease severity in amyotrophic lateral sclerosis [HuEx-1_0-st]

Project description:Objective: An intronic GGGGCC-repeat expansion of C9ORF72 is the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The mechanism of neurodegeneration is unknown, but a direct effect on RNA processing mediated by RNA foci transcribed from the repeat sequence has been proposed. Results: Gene level analysis revealed a number of differentially expressed networks and both cell types exhibited dysregulation of a network functionally enriched for genes encoding ‘RNA splicing’ proteins. There was a significant overlap of these genes with an independently generated list of GGGGCC-repeat protein binding partners. At the exon level, in lymphoblastoid cells derived from C9ORF72-ALS patients splicing consistency was lower than in lines derived from non-C9ORF72 ALS patients or controls; furthermore splicing consistency was lower in samples derived from patients with faster disease progression. Frequency of sense RNA foci showed a trend towards being higher in lymphoblastoid cells derived from patients with shorter survival, but there was no detectable correlation between disease severity and DNA expansion length. Significance: Up-regulation of genes encoding predicted binding partners of the C9ORF72 expansion is consistent with an attempted compensation for sequestration of these proteins. A number of studies have analysed changes in the transcriptome caused by C9ORF72 expansion, but to date findings have been inconsistent. As a potential explanation we suggest that dynamic sequestration of RNA processing proteins by RNA foci might lead to a loss of splicing consistency; indeed in our samples measurement of splicing consistency correlates with disease severity. Gene expression profiling utilised total RNA extracted from lymphoblastoid cell lines derived from human ALS patients (n=56), and controls (n=15). Thirty-one of the ALS patients had a mutation of C9ORF72.

2015-05-08 | E-GEOD-68607 | biostudies-arrayexpress

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