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Inhibition of RNA splicing triggers CHMP7 nuclear entry impacting TDP-43 function and leading to onset of ALS (eCLIP).

ABSTRACT: Inhibition of RNA splicing triggers CHMP7 nuclear entry impacting TDP-43 function and leading to onset of ALS (eCLIP).

PROVIDER: PRJNA1069013 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27726257.fastq.gz	Fastqsanger.gz
	SRR27726258.fastq.gz	Fastqsanger.gz
	SRR27726259.fastq.gz	Fastqsanger.gz
	SRR27726260.fastq.gz	Fastqsanger.gz
	SRR27726261.fastq.gz	Fastqsanger.gz

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Inhibition of RNA splicing triggers CHMP7 nuclear entry impacting TDP-43 function and leading to onset of ALS

Project description:Inhibition of RNA splicing triggers CHMP7 nuclear entry impacting TDP-43 function and leading to onset of ALS

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Inhibition of RNA splicing triggers CHMP7 nuclear entry impacting TDP-43 function and leading to onset of ALS (RNA-Seq).

Project description:Inhibition of RNA splicing triggers CHMP7 nuclear entry impacting TDP-43 function and leading to onset of ALS (RNA-Seq).

| PRJNA1069014 | ENA

Inhibition of RNA splicing triggers CHMP7 nuclear entry impacting TDP-43 function and leading to onset of ALS (eCLIP).

Project description:Amyotrophic lateral sclerosis (ALS) has been linked to nucleoporin loss in patient neurons. In the ESCRT-III pathway, CHMP7 protein accumulation in the nucleus triggers ALS by damaging nuclear pores and disrupting cellular transport. Genes controlling CHMP7's nuclear presence remain unidentified. Our Craft-ID analysis revealed that RNA binding proteins involved in assembling small nuclear ribonucleoprotein particles control CHMP7 nuclear localization. This regulation ultimately impacts splicing processes and can lead to pore injury. Using IP-MS, we discovered that CHMP7 interacts with the survival of motor neuron (SMN) complex (SmD1-3, Gemins), mediated by U1 snRNP and direct interactions between CHMP7. Reducing expression of the core SMN complex component SmD1 was observed in ALS iPSC- Motor Neurons (MNs), affecting CHMP7 localization. However, restoring its levels can rescue the cytoplasmic localization of CHMP7 in sALS iPSC-MNs. Our discoveries hint at an early ALS pathway involving SMN core complex dysregulation, influencing disease onset.

2024-11-01 | GSE254209 | GEO

Deciphering RBP - alternative splicing networks in ALS iPSC-MN: TDP-43, NOVA1, NOVA2 and RBFOX2 eCLIP-seq

Project description:We produced enhanced cross-linking immunoprecipitation (eCLIP) sequencing data of the RNA binding proteins (RBP) TDP-43, NOVA1, NOVA2 and RBFOX2 in iPSC motor neurons of two healthy control individuals, respectively.

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Inhibition of RNA splicing triggers CHMP7 nuclear entry impacting TDP-43 function and leading to onset of ALS

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-10-31 | GSE254210 | GEO

Inhibition of RNA splicing triggers CHMP7 nuclear entry impacting TDP-43 function and leading to onset of ALS (RNA-Seq).

2024-11-01 | GSE254208 | GEO

TDP-43 represses cryptic exon inclusion in FTD/ALS gene UNC13A

Project description:Through splicing analysis of a publicly available RNA-Seq dataset, we discovered TDP-43 represses a cryptic exon splicing event in UNC13A, a gene that had been associated with FTD/ALS through GWA studies. To confirm the sequences of the cryptic exons, we used shRNA to reduce TDP-43 levels in iPSC-derived motor neurons (iPSC-MNs) and by amplicon sequencing the RT-PCR product, we observed the insertion in cells with TDP-43 depletion but not in control shRNA-treated cells. Through sequence alignment, we verified the sequences of the cryptic exons.

2021-12-04 | GSE182976 | GEO

TDP-43 loss induces cryptic polyadenylation in ALS/FTD [slamseq-i3-cortical]

Project description:Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of ALS, occurring in over 97% of cases. A key consequence of TDP-43 nuclear loss is the de-repression of cryptic exons. Whilst TDP-43 regulated cryptic splicing is increasingly well catalogued, cryptic alternative polyadenylation (APA) events, which define the 3’ end of last exons, have been largely overlooked, especially when not associated with novel upstream splice junctions. We developed a bioinformatic pipeline to reliably identify distinct APA event types: alternative last exons (ALE), 3’UTR extensions (3’Ext) and ‘ composite ’ intronic polyadenylation (IPA) events. We identified novel neuronal cryptic APA sites induced by TDP-43 loss of function by systematically applying our pipeline to a compendium of publicly available and in house datasets. We find that TDP-43 binding sites and target motifs are enriched at these cryptic events and that TDP-43 can have both repressive and enhancing action on APA. Importantly, all categories of cryptic APA can also be identified in ALS and FTD post mortem brain regions with TDP-43 proteinopathy underlining their potential disease relevance. RNA-seq and Ribo-seq analyses indicate that distinct cryptic APA categories have different downstream effects on transcript and translation. Intriguingly, cryptic 3’Exts occur in multiple transcription factors, such as ELK1 , SIX3, and TLX1, and lead to an increase in RNA stability. 3’Exts are localised to the cytoplasm and neurites and translated leading to an increase in wild-type protein levels. In summary, we demonstrate that TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events and we expand the palette of TDP-43 loss consequences by showing this can also lead to an increase in normal protein translation.

2025-05-30 | GSE296716 | GEO

TDP-43 loss induces cryptic polyadenylation in ALS/FTD [humphrey-i3-cortical]

2025-05-30 | GSE296714 | GEO

ALS associated TDP-43 aggregates drive innate and adaptive immune cell activation

Project description:Amyotrophic lateral sclerosis is the most common and fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 aggregates elicit immune responses remains underexplored. In this study, we demonstrate that TDP-43 aggregates are internalized by antigen presenting cell populations, cause vesicle rupture, and drive innate and adaptive immune cell activation by way of antigen presentation. Using a multiplex imaging platform, we observed enrichment of activated microglia/macrophages in ALS white matter that correlated with phosphorylated TDP-43 accumulation, CD8 T-cell infiltration, and major histocompatibility complex expression. Taken together, this study sheds light on a novel cellular response to TDP43 aggregates through an immunological lens.

2025-04-07 | GSE293662 | GEO

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