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ALS-associated RNA binding proteins converge on UNC13A transcription through regulation of REST

ABSTRACT: ALS-associated RNA binding proteins converge on UNC13A transcription through regulation of REST

PROVIDER: PRJNA1238221 | ENA |

REPOSITORIES: ENA

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ALS-associated RNA binding proteins converge on UNC13A transcription through regulation of REST

Project description:Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration. We demonstrate that ALS-associated RNA-binding proteins (RBPs)—MATR3, FUS, and hnRNPA1—regulate UNC13A transcription via REST mRNA stabilization. Loss of these RBPs increases REST levels, repressing UNC13A transcription and implicating synaptic dysfunction in ALS pathogenesis.

2025-07-21 | GSE292352 | GEO

Characterization of human healthy i3 lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype

Project description:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. Neurodegeneration in ALS might be driven by proteotoxicity or neuroinflammation, which have also been proposed to be promoted by toxic components of the cerebrospinal fluid (CSF). We investigated the possible toxicity of ALS CSF on healthy induced pluripotent stem cells (iPSC)-derived integrated, inducible, and isogenic lower motor neurons (i3LMNs). CSFs were obtained from ALS patients homozygous for the risk UNC13A rs12608932 single nucleotide polymorphism (CC) and for the corresponding major allele (AA), ALS patients with C9ORF72 hexanucleotide repeat expansion, and individuals affected by normal pressure hydrocephalus (NPH), a non-degenerative condition, as controls (ND). Chronic sodium arsenite (ARS) treatment was used as positive control of oxidative stress. We found that 10 % ALS CSF treatment for 48 h was not sufficient to induce significant alterations in viability, autophagic flux, axonal degeneration, DNA damage, and Golgi apparatus integrity in healthy i3LMNs, in contrast to ARS treatment. Only UNC13A CC CSF significantly increased protein aggregation and Golgi apparatus fragments dimension. RNA-sequencing revealed that all ALS and ND CSFs induced expression changes of few genes, while chronic ARS deregulated the expression of thousands of genes, mostly involved in inflammation and synapse biology. In this work, we demonstrated that in our experimental settings only UNC13A CC CSF induced some ALS-associated pathological features in healthy i3LMNs. Further studies will be required to elucidate the mechanistic link between the risk UNC13A genotype and CSF composition and toxicity.

2025-04-18 | GSE291052 | 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 represses cryptic exon inclusion in FTD/ALS gene UNC13A

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

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Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs

Project description:This SuperSeries is composed of the following subset Series: GSE40649: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (microarray) GSE40651: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (CLIP-Seq) GSE40652: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (RNA-Seq) Refer to individual Series

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TDP-43 iCLIP of cells transfected with UNC13A minigene

Project description:UNC13A contains a cryptic exon which is normally repressed by TDP-43. To better understand the mechanism by which TDP-43 represses this cryptic splicing, and how common SNPs (rs12973192(G) and rs12608932(C)) perturb this regulation, we transfected HEK293T cells with minigenes featuring UNC13A exons 20 and 21, and intron 20. We used two variants of the minigene: one with rs12973192(C) and rs12608932(G) (2x healthy) and the other with rs12973192(G) and rs12973192(C) (2x risk), then performed TDP-43 iCLIP on these cells. We used two replicates for each.

2022-03-24 | E-MTAB-10297 | biostudies-arrayexpress

Nanopore sequencing of UNC13A from SHSY5Y and patient RNA

Project description:UNC13A contains a novel cryptic exon which is expressed upon TDP-43 knockdown. However, it also features TDP-43 regulated intron retention of a downstream intron. To investigate the correlation of these two events, we performed Nanopore sequencing of amplicons from SHSY5Y cells with inducible TDP-43 knockdown, and FTD patient RNA samples

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Distinct brain transcriptome profiles in c9orf72-associated and sporadic ALS

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Characterization of human healthy i3 lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype

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Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis

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