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Knocking out C9ORF72 exacerbates axonal trafficking defects associated with hexanucleotide repeat expansion and reduces levels of heat shock proteins II

ABSTRACT: Knocking out C9ORF72 exacerbates axonal trafficking defects associated with hexanucleotide repeat expansion and reduces levels of heat shock proteins II

PROVIDER: PRJNA601467 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10899792.fastq.gz	Fastqsanger.gz
	SRR10899793.fastq.gz	Fastqsanger.gz
	SRR10899794.fastq.gz	Fastqsanger.gz
	SRR10899795.fastq.gz	Fastqsanger.gz

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Similar Datasets

Knocking out C9ORF72 exacerbates axonal trafficking defects associated with hexanucleotide repeat expansion and reduces levels of heat shock proteins I

Project description:Knocking out C9ORF72 exacerbates axonal trafficking defects associated with hexanucleotide repeat expansion and reduces levels of heat shock proteins I

| PRJNA601468 | ENA

Knocking out C9ORF72 exacerbates axonal trafficking defects associated with hexanucleotide repeat expansion and reduces levels of heat shock proteins I

Project description:iPSCs with mutant C9ORF72 were edited using CRISPR/Cas9 (1) to knockout C9ORF72 or, alternatively, (2) to correct the ALS mutation, followed by differentiation into motor neurons.

2020-01-17 | GSE143743 | GEO

Knocking out C9ORF72 exacerbates axonal trafficking defects associated with hexanucleotide repeat expansion and reduces levels of heat shock proteins II

Project description:wild type iPSCs were edited using CRISPR/Cas9 to knockout C9ORF72 followed by differentiation into neurons.

2020-01-17 | GSE143744 | GEO

Profiling nucleo/cytoplasmic distribution of mRNAs identifies a role for the Golgi-to-ER trafficking in C9orf72 toxicity

Project description:Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in C9orf72, the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates the nucleocytoplasmic distribution of proteins and RNAs, thereby affecting their functions. We have previously reported that the expression of G4C2 hexanucleotide repeats in cultured human and mouse cells caused a marked accumulation of poly(A) mRNAs in cell nuclei, suggesting that mRNA trafficking is impaired by expanded C9orf72-ALS repeats. To further characterize the process, in this work we set out to systematically identify the specific mRNAs that are altered in their nucleocytoplasmic distribution in the presence of C9orf72-ALS repeats. Results from RNAseq profiling of nuclear and cytoplasmic RNA fractions obtained from cells expressing G4C231 repeats show a significant accumulation of mRNAs in the nuclei of G4C231 cells, further suggesting that nuclear retention of mRNAs is a major effect of C9orf72 expanded repeats expression. Interestingly, pathway analysis shows that mRNAs involved in ER-to-Golgi trafficking are particularly enriched among the identified mRNAs. Most importantly, functional studies in cultured cells and Drosophila indicate that the membrane trafficking route regulated by ARFGAP1, a GTPase-activating protein that associates with Golgi, is specifically affected by expanded C9orf72 repeats, as well as by C9orf72-related dipeptide repeat proteins (C9-DPRs), pointing to ER-to-Golgi vesicle-mediated transport as a target of C9orf72 toxicity.

2023-08-21 | GSE235448 | GEO

C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project

Project description:C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project

| PRJNA497344 | ENA

C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project

Project description:C9ORF72 Hexanucleotide Repeat Sequence Genotyping Project

| PRJNA497345 | ENA

Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins.

Project description:In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS, but the mechanism of pathogenesis is largely unknown with both gain- and loss-of-function mechanisms being proposed. To better understand C9ORF72-ALS pathogenesis, we generated isogenic induced pluripotent stem cells. MNs with HRE in C9ORF72 showed decreased axonal trafficking compared with gene corrected MNs. However, knocking out C9ORF72 did not recapitulate these changes in MNs from healthy controls, suggesting a gain-of-function mechanism. In contrast, knocking out C9ORF72 in MNs with HRE exacerbated axonal trafficking defects and increased apoptosis as well as decreased levels of HSP70 and HSP40, and inhibition of HSPs exacerbated ALS phenotypes in MNs with HRE. Therefore, we propose that the HRE in C9ORF72 induces ALS pathogenesis via a combination of gain- and loss-of-function mechanisms.

| S-EPMC7066330 | biostudies-literature

C9orf72 hexanucleotide repeat expansions impair microglial response in models of ALS [RNA]

Project description:The involvement of microglia and neuroinflammation in amyotrophic lateral sclerosis (ALS) is well recognized, but the precise underlying molecular mechanisms remain elusive. We generated single-nuclei transcriptomic profiles from the spinal cord and motor cortex of sporadic (sALS) and C9orf72 (C9-ALS) ALS patients. We confirmed that C9orf72 is highly expressed in microglia and observed that the hexanucleotide repeat expansion (HRE) results in haploinsufficiency specifically in these cells. Whereas sALS microglia transitioned towards classically defined disease-associated transcriptomic profiles, C9orf72 HRE microglia exhibited a diminished response, with alterations in phagocytic and lysosomal pathways. We confirmed these observations using a human microglia xenograft model, which showed that C9orf72 loss-of-function leads to a reduced baseline activation, with lower expression of antigen-presenting related genes. We also confirmed the alterations in the endolysosomal pathway in C9orf72-HRE and C9orf72-deficient induced pluripotent stem cell (iPSC)-derived microglia. In addition, we observed a diminished response of astrocytes in C9orf72-HRE carriers and provided an extensive map of dysregulated ligand-receptor pairs in microglia and astrocyte indicating an altered cell-cell communication in both C9orf72 and sALS. This complex cellular interplay highlights variations in the cellular substrate of sporadic and inherited forms of ALS, providing valuable insights for patient stratification and for selecting appropriate treatments.

2025-10-20 | GSE302295 | GEO

C9orf72 hexanucleotide repeat expansions impair microglial response in models of ALS [scRNA]

2025-10-20 | GSE302319 | GEO

C9ORF72 interaction with cofilin modulates actin dynamics in motoneurons

Project description:Intronic hexanucleotide expansions in C9ORF72 are common in ALS and FTLD, but it is unknown whether loss of function, toxicity by the expanded RNA or dipeptides from non ATG-initiated translation are responsible for the pathophysiology. We determined the interactome of C9ORF72 in motoneurons and found that C9ORF72 is present in a complex with cofilin and other actin binding proteins. Phosphorylation of cofilin is enhanced in C9ORF72 depleted motoneurons, in patient derived lymphoblastoid cells, iPS cell derived motoneurons and post-mortem brain samples from ALS patients. C9ORF72 modulates the activity of the small GTPases Arf6 and Rac1, resulting in enhanced activity of LIMK1/2. This results in reduced axonal actin dynamics in C9ORF72 depleted motoneurons. Dominant negative Arf6 rescues this defect, suggesting that C9ORF72 acts as a modulator of small GTPases in a pathway that regulates axonal actin dynamics.

2016-09-30 | PXD004913 | Pride

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