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PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS [1]

ABSTRACT: RNA sequencing analysis of human iPSC-derived motor neurons generated from one C9ORF72 ALS/FTD patient line, treated with DMSO or Apilimod. The goal of this study is to evaluate the effect of PIKFYVE inhibitor in rescuing ALS motor neuron degeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221015 | GEO | 2022/12/18

REPOSITORIES: GEO

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PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS [2]

Project description:RNA sequencing analysis of human iPSC-derived motor neurons generated from two C9ORF72 ALS/FTD patient lines, treated with negative control ASO (NC ASO) or PIKFYVE ASO. The goal of this study is to evaluate the effect of PIKFYVE suppression in rescuing ALS motor neuron degeneration.

2022-12-18 | GSE221016 | GEO

SYF2 Suppression Mitigates Neurodegeneration in Models of Diverse Forms of ALS

Project description:RNA sequencing analysis of human induced motor neurons generated from a C9ORF72 ALS patient line and its isogenic control, treated with siRNA targetting SYF2. The goal of this study is to evaluate the process of SYF2 suppression in rescuing ALS motor neuron degeneration.

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PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS

Project description:PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS

| PRJNA912584 | ENA

PIKfyve controls dendritic cell function and tumor immunity II

Project description:To understand the mechanism of Pikfyve inhibition in dendritic cells, we cultured conventional dendritic cells isolated from the bone marrow of wild-type mice and performed transcriptome profiling on RNA extracted from cells treated with DMSO or apilimod for 3 or 8 hours on Day 6 in culture. Taken together, these data demonstrate the PIKfyve mediates suppression of DC transcriptional maturation programs through the alternate/non-canonical NF-κB regulatory pathway.

2023-06-26 | GSE235599 | GEO

A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD

Project description:An abnormal expansion of a G4C2 hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we developed a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.

2024-11-28 | GSE250633 | GEO

A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD

Project description:An abnormal expansion of a GGGGCC hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we developed a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform effectively curbed the expression of the GGGGCC repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci and reversed transcriptional deficits. This high-fidelity Cas13 variant possessed improved transcriptome-wide specificity compared to its native form and mediated efficient targeting in motor neuron-like cells derived from a patient with ALS. Our results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.

2024-12-08 | GSE283702 | GEO

A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD

2024-11-28 | GSE251822 | GEO

PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS [1]

Project description:PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS [1]

| PRJNA912588 | ENA

PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS [2]

Project description:PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS [2]

| PRJNA912589 | ENA

Therapeutic manipulation of SRSF1 mitigates genome-wide transcriptome alterations and neuronal hyperexcitability in C9ORF72-linked amyotrophic lateral sclerosis

Project description:Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to relentless paralysis and death usually within a few years from symptom onset. Thousands of RNA molecules with roles in multiple cellular pathways are compromised in disease challenging the identification of alterations causing pathogenesis over downstream changes consequent to neurodegeneration. We recently showed that partial depletion of SR-rich splicing factor SRSF1 inhibits the nuclear export of pathological C9ORF72-repeat transcripts and subsequent translation of dipeptide-repeat proteins in patient-derived neurons and Drosophila, providing in turn a promising strategy of neuroprotection for the most common form of ALS. While the roles of SRSF1 remain poorly characterised in neurons, its therapeutic manipulation offers a rare opportunity to identify disease-modifying gene expression changes. Here, we report diseased and neuroprotected transcriptomes from human-derived neurons and Drosophila heads. Strikingly, while the depletion of SRSF1 has limited effects on genome-wide expression, splicing and nuclear export of RNAs, reversal of 90 disease-modifying transcripts were identified over 2,000 RNA changes in human disease. Functional validation further demonstrated that conserved potassium intermediate/small conductance calcium-activated KCNN channel inhibitors mitigate C9ORF72-ALS mediated hyperexcitability and death of human motor neurons as well as Drosophila motor deficits. Our data support efficacy and safety of SRSF1 manipulation as a therapeutic approach leading to rescue of multiple biological processes without disrupting neuronal transcriptomes. In addition to a potential new therapeutic target for pharmacological inhibition, we also identified in vitro and in vivo disease-modifying gene expression signatures to guide the development of new biomarkers and novel therapeutic approaches in C9ORF72-ALS/FTD.

2021-07-19 | GSE139900 | GEO

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