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A regulatory circuitry between the Gria2 mRNA and miR-409/miR-495 is altered in mESC-derived motor neurons carrying an ALS-associated FUS mutation

ABSTRACT: Mutations in FUS/TLS have been genetically associated to Amyotrophic Lateral Sclerosis (ALS). Since FUS is a multifunctional protein involved in the biogenesis and activity of several types of RNAs, the understanding of the molecular basis of ALS pathogenesis should take into account both direct effects of FUS mutation through gain- and loss-of function mechanisms as well as indirect effects due to the crosstalk between different classes of RNAs. To identify how FUS alterations impinge on MN-specific RNA-based circuitries, we performed a transcriptome profiling of small- and long- RNAs of motor neurons derived in vitro from differentiation of mouse Embryonic Stem Cells carrying a knock-in FUS-P517L mutation, corresponding to the human FUS-P525L. Combining ontological, predictive and molecular analyses we found an interesting inverse correlation between several classes of deregulated miRNAs and their corresponding mRNA targets. Among them we validated a circuitry in which the up-regulation of miR-409-3p and miR-495-3p produced the down-regulation of the Gria2 mRNA. This cross-talk is relevant for the ALS pathogenesis since Gria2, encoding for a subunit of the glutamate AMPA receptor, has been already linked to ALS through an excitotoxicity mechanism. Notably, this circuitry resulted deregulated also in heterozygous conditions, which match the genetic background of the human pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE101097 | GEO | 2018/01/31

REPOSITORIES: GEO

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A study of how homozygous ALS-linked FUS P525L mutations perturb transcriptome profile in human iPSC-derived microglia

Project description:Purpose: The FUS P525L mutation is highly penetrant and causes ALS cases with earlier disease onset and more aggressive progression. This study aims to understand the impact of P525L mutations in microglia during ALS pathogenesis. We compare the transcriptome (RNA-seq) of P525L mutations to the wildtype and isogenic controls to derive the differentially perturbed genes. Methods: Transcriptome profiles of human iPSC-derived microglia with gentoype of wild-type (WT), isogenic control (eCtrl), P525L homozygous (P525LHom), P525L heterozygous (P252LHet) and null deletion (KO) were generated using Illumina HiSeq2000 by multiplexed paired-read run with 100 cycles. Pass-QC sequencing reads were mapped to the human genome (hg19) using the OmicSoft ArrayStudio software followed by differential gene expression analysis via DESeq2 package. Results: Homozygous P525L mutations perturb the transcriptome profile where many differentially expressed genes are associated with microglial functions. Specifically, dysregulation of several chemoreceptor genes leads to altered chemoreceptor-activated calcium signaling. Conclusions: Our study underscores the cell- autonomous effects of the ALS-linked FUS P525L mutation in a human microglia model.

2022-02-03 | GSE172459 | GEO

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2020-10-21 | GSE139263 | GEO

Axonal transcriptome reveals upregulation of PLK1 as a protective mechanism in response to increased DNA damage in FUSP525L spinal motor neurons

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2021-06-23 | E-MTAB-8456 | biostudies-arrayexpress

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

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