Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Motor Neuron m6A Repertoire Governs Neuronal Homeostasis and Augmented m6A Production Mitigates ALS Symptom Manifestation [snMultiome-seq]

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a swiftly progressive and fatal neurodegenerative ailment marked by the degenerative motor neurons (MNs). Why MNs are specifically susceptible in predominantly sporadic cases remains enigmatic. Here, we demonstrated N6-methyladenosine (m6A), an RNA modification catalyzed by the METTL3/METTL14 methyltransferase complex, as a pivotal contributor to ALS pathogenesis. By conditional knockout Mettl14 in murine MNs, we recapitulate almost the full spectrum of ALS disease characteristics. Mechanistically, pervasive m6A hypomethylation triggers dysregulated expression of high-risk genes associated with ALS and an unforeseen reduction of chromatin accessibility in MNs. Additionally, we observed diminished m6A levels in induced pluripotent stem cell (iPSC)-derived MNs from familial and sporadic ALS patients. Restoring m6A equilibrium via a small molecule or gene therapy significantly preserves MNs from degeneration and mitigates motor impairments in ALS iPSC-derived MNs and murine models. Our study presents a substantial stride towards identifying pioneering efficacious ALS therapies via RNA modifications.

ORGANISM(S): Mus musculus

PROVIDER: GSE290242 | GEO | 2025/04/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcriptomic Validation of ALS-Derived Motor Neurons Following m6A Hypomethylation Restoration

Project description:In this experiment, we investigated transcriptomic alterations in iPSC-derived motor neurons from ALS patients following the restoration of m6A hypomethylation to mitigate neurodegenerative processes.

2025-04-30 | GSE290244 | GEO

095497af-5a52-4df9-8c01-8e6d42010aa4 - samples

Project description:iPSC-derived motor neurons form sporadic ALS and Controls. 4 sALS iPSC lines and 4 Ctrl iPSC lines.

| EGAD00001008424 | EGA

Targeting low levels of MIF expression as a potential therapeutic strategy for ALS

Project description:Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neurons (MNs) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low in spinal MNs, inhibits mutant SOD1 misfolding and toxicity. In this study, we show that a single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1G37R mice, significantly improved their motor function, delayed disease progression and extended survival. Moreover, MIF treatment reduced neuroinflammation and misfolded SOD1 accumulation, rescued MNs and corrected dysregulated pathways as observed by proteomics and transcriptomics. Furthermore, we revealed low MIF levels in human induced pluripotent stem cell derived MNs from familial ALS patients with different genetic mutations, as well as in post-mortem tissues of sporadic ALS patients. Our findings indicate that peripheral MIF administration may provide a potential therapeutic mechanism for modulating misfolded SOD1 in vivo and disease outcome in ALS patients.

2024-01-11 | GSE246397 | GEO

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

Project description:Amyotrophic lateral sclerosis (ALS) is linked to the reduction of certain nucleoporins in neurons. Increased nuclear localization of charged multivesicular body protein 7 (CHMP7), a protein involved in nuclear pore surveillance, has been identified as a key factor damaging nuclear pores and disrupting transport. Using CRISPR-based microRaft, followed by gRNA identification (CRaft-ID), we discovered 55 RNA-binding proteins (RBPs) that influence CHMP7 localization, including SmD1, a survival of motor neuron (SMN) complex component. Immunoprecipitation-mass spectrometry (IP-MS) and enhanced crosslinking and immunoprecipitation (CLIP) analyses revealed CHMP7’s interactions with SmD1, small nuclear RNAs, and splicing factor mRNAs in motor neurons (MNs). ALS induced pluripotent stem cell (iPSC)-MNs show reduced SmD1 expression, and inhibiting SmD1/SMN complex increased CHMP7 nuclear localization. Crucially, overexpressing SmD1 in ALS iPSC-MNs restored CHMP7’s cytoplasmic localization and corrected STMN2 splicing. Our findings suggest that early ALS pathogenesis is driven by SMN complex dysregulation.

2024-01-24 | MSV000093914 | MassIVE

Noncoding RNAs induce TDP43 pathology in the ALS-iPSC models

Project description:Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) degenerative disease with a major pathological feature of cytoplasmic TDP-43 aggregation. However, the mechanisms underlying TDP-43 proteinopathy are still largely unknown. We performed in vitro differentiation of ALS-induced pluripotent stem cells (ALS-iPSCs; carrying the TDP-43M337V mutation) and isogenic controls and found upregulation of paraspeckle-associated lncRNA NEAT1 isoforms in the ALS-iPSC-derived MNs (ALS-iPSC-MNs). Intriguingly, the upregulated NEAT1 isoforms were mislocalized to the cytoplasm of ALS-iPSC-MNs, and the cytoplasmic NEAT1 provoked TDP-43 and TDP-43M337V liquid-liquid phase separation, generating long-lived protein condensates. These condensates had reduced mobility and were converted into aggregates, finally co-aggregating with phospho-TDP-43. Disruption of NEAT1 expression reduced its cytoplasmic levels and also reduced the levels of TDP-43/TDP-43M337V condensates. In 3D neuromuscular organoids with the TDP-43M337V mutation, treatment with NEAT1-antisense oligonucleotides (NEAT1-ASO) promoted neuromuscular junction formation and function, as well as muscle contractility. Furthermore, treatment of TDP-43Q331K mice with Neat1-ASO attenuated TDP-43 pathology in spinal cord and preserved motor function. These findings suggest that NEAT1 plays an important role in TDP-43-associated pathology, and NEAT1-ASO may attenuate pathological TDP-43 aggregation to prevent motor neuron degeneration and muscle weakness in ALS.

2024-11-24 | GSE189470 | GEO

Deciphering RBP - alternative splicing networks in ALS iPSC-MN: patient and control datasets

Project description:We produce RNA-seq datasets of iPSC-derived motor neurons (iPSC-MN) from healthy controls and sporadic ALS patients and controls and familial ALS patients with pathogenic variants in TARDBP.

| EGAS00001005879 | EGA

M6A reduction relieves FUS-associated ALS granules [m6A-IP]

Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motorneurons (MN) degeneration1. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by mutant protein aggregation, among which the RNA binding protein FUS. In this work we show that such inclusions are significantly reduced in number and dissolve faster when the RNA m6A content is diminished as a consequence of the m6A writer METTL3 knock-down. These effects were obtained observed both in neuronal cell lines and in iPSC-derived human motor neurons expressing mutant FUS. Importantly, stress granules formed in mutant conditionswhen mutant FUS is expressed/ALS condition showed a distinctive transcriptome with respect to control cells; interestingly, after METTL3 downregulation, it reverted to similar to control. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, a well characterized inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.

2024-05-06 | GSE242770 | GEO

Microarray analysis identifies the gene signature of surviving motor neurons in human SOD1-related motor neuron disease

Project description:Gene expression profiling has been performed previously on motor cortex and spinal cord homogenates and of sporadic ALS cases and controls, to identify genes and pathways differentially expressed in ALS. More recent studies have combined the use of laser capture microdissection (LCM) with gene expression profiling to isolate the motor neurons from the surrounding cells, such as microglia and astrocytes, in order to determine those genes differentially expressed in the vulnerable cell population – i.e. motor neuron. The aim of the present study is to combine LCM and microarray analysis to determine those genes and pathways differentially expressed in MNs from human SOD1-related MND and to establish potential pathways for therapeutic intervention. Keywords: Human motor neurons The aim of this study was to determine the gene expression profiles from a small subset of cases which all carry mutations in the SOD1 gene. Expression profiles from isolated motor neurons in SOD1-related ALS cases were compared to those from control motor neurons, in order to establish the pathways implicated in SOD1-related motor neuronal cell death. The 'control' samples were originally submitted to GEO as GSE19332.

2011-01-01 | E-GEOD-20589 | biostudies-arrayexpress

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

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