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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).

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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

Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modifications [eCLIP-seq]

Project description:Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here, we identify the RNA-binding TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems. Dysregulated nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 is shown to be present in HD mice and human brains with TDP-43 co-localizing with HTT nuclear aggregate-like bodies distinct from mutant HTT inclusions and from previously observed TDP-43 pathologies. The binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in the striatum from HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a mechanism underlying alternative splicing in HD and highlights the critical nature of TDP-43 loss of function across multiple neurodegenerative diseases.

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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.

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TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss-of-function of TDP-43

Project description:Cytoplasmic aggregation and nuclear depletion of TDP-43 are hallmarks of several age-related neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been a major challenge. Here, we produced amyloid-like fibrils from the recombinant low-complexity-domain of TDP-43, and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cell lines and iPSC-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin- and p62-accumulation, and recruit nuclear endogenous TDP-43 leading to nuclear-loss-of-function-driven disease-specific cryptic splicing defects. Cytoplasmic TDP-43 aggregates exhibit, with time, distinct heterogeneous morphologies as in patients including compacted, filamentous or fragmented, through the activation of cellular protein clearance pathways. Cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify templated aggregation of TDP-43 as a key mechanism driving both cytoplasmic gain- and nuclear-loss-of-function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.

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RBM33 eCLIP

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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 binds to RNA G-quadruplex structure and regulates mRNA stability and translation

Project description:TDP-43 is a hallmark protein associated with neurodegenerative diseases. Recent studies revealed TDP-43 as an RNA G-quadruplex (rG4) binding protein, impacting mRNA transport and function. However, our understanding on the interaction between TDP-43 and RNA secondary structure remains poorly understood. Additionally, reports on specific rG4 targets regulated by TDP-43 are limited. Herein, we show that TDP-43 exhibits a preference for binding to the rG4 structure under K+ condition by a high-throughput RNA Bind-n-Seq method. Besides, we find that loss of TDP-43 contributes to a decrease in mRNA structure in the transcriptome by using the newly developed SHALiPE-seq technology. By analyzing the SHALiPE-seq data of TDP-43 binding sites, we further demonstrate that the reduction in structural complexity is likely due to the loss of TDP-43 binding to the RNA targets, especially in the 3'UTR. Importantly, our transcript-specific investigation reveals that TDP-43 binds to a novel rG4 structure in the 3'UTR of SLC1A5 mRNA, promoting the mRNA stability and translation. Our findings not only offer new insights into the role of TDP-43 in regulating RNA structure such as rG4, but also contribute to a better understanding of its broader functions and provide potential targets for therapeutic strategies in TDP43-related diseases.

2025-09-01 | GSE272797 | GEO

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