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Combining multi-omics and drug perutbation profiles to identify novel treatments that improve disease phenotypes in spinal muscular atrophy [RNA-seq]

ABSTRACT: We used an in-depth and parallel approach combining proteomics, transcriptomics and the drug pertubational dataset Connectivity Map (CMap) to identify differentially expressed (DE) transcripts and proteins in skeletal muscle of the severe Taiwanese Smn‍-‍/‍-‍;SMN2‍ SMA mice that could potentially be restored by known and available pharmacological compounds. This strategy uncovered several potential therapeutic candidates, including harmine, which was further evaluated in cell and animal models, showing an ability to restore molecular networks and improve several disease phenotypes, including SMN expression and lifespan.

ORGANISM(S): Mus musculus

PROVIDER: GSE150510 | GEO | 2020/05/14

REPOSITORIES: GEO

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SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

Project description:Characterization of the selectivity of SMN splicing modifiers in SMA type I fibroblasts by RNASeq In total 12 samples were analyzed, divided into four distinct groups (treated with SMN-C3 @ 500 nM; controls for SMN-C3; treated with SMN-C1 @ 100 nM; controls for SMN-C1) containing 3 replicates each.

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SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

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SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy

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2023-11-27 | MTBLS8784 | MetaboLights

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Project description:Spinal muscular atrophy is the leading genetic cause of infant mortality and is caused by homozygous loss of the SMN1 gene. We investigated global transcriptome changes in the spinal cord of inducible SMA mice. SMN depletion caused widespread retention of introns with weak splice sites or belonging to the minor (U12) class. We further demonstrated accumulation of DNA double strand breaks in the spinal cord of SMA mice and in human SMA cell culture models. DNA damage was partially rescued by suppressing the formation of R-loops, which accumulated over retained introns. We propose that instead of single gene effects, pervasive splicing defects caused by SMN deficiency trigger a global DNA damage and stress response, thus compromising motor neuron survival.

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Project description:Proximal spinal muscular atrophy (SMA) is an early onset, autosomal recessive motor neuron disease caused by loss of or mutation in SMN1 (survival motor neuron 1). Despite understanding the genetic basis underlying this disease, it is still not known why motor neurons (MNs) are selectively affected by the loss of the ubiquitously expressed SMN protein. Using a mouse embryonic stem cell (mESC) model for severe SMA, the RNA transcript profiles (transcriptomes) between control and severe SMA (SMN2+/+;mSmn-/-) mESC-derived MNs were compared in this study using massively parallel RNA sequencing (RNA-Seq). The MN differentiation efficiencies between control and severe SMA mESCs were similar. RNA-Seq analysis identified 3094 upregulated and 6964 downregulated transcripts in SMA mESC-derived MNs when compared against control cells. Pathway and network analysis of the differentially expressed RNA transcripts showed that pluripotency and cell proliferation transcripts were significantly increased in SMA MNs while transcripts related to neuronal development and activity were reduced. The differential expression of selected transcripts such as Crabp1, Crabp2 and Nkx2.2 was validated in a second mESC model for SMA as well as in the spinal cords of low copy SMN2 severe SMA mice. Furthermore, the levels of these selected transcripts were restored in high copy SMN2 rescue mouse spinal cords when compared against low copy SMN2 severe SMA mice. These findings suggest that SMN deficiency affects processes critical for normal development and maintenance of MNs. RNA profiles were generated from FACS-purified control and SMA mESC-derived motor neurons (n=3/genotype) by deep sequencing using Illumina HighSeq 2500

2014-09-08 | E-GEOD-56284 | biostudies-arrayexpress

Suppression of NCALD protects against spinal muscular atrophy by restoring impaired endocytosis

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2022-08-24 | PXD034596 | Pride

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Project description:Spinal muscular atrophy (SMA) is characterized by low levels of survival motor neuron (SMN) protein and loss of motor neurons (MN); however, the underlying mechanism that links SMN deficiency to selective motor neuronal dysfunction is still largely unknown. We present here, for the first time, a comprehensive quantitative mass spectrometry study that covers the development of iPSC-derived MNs from both healthy individuals and SMA patients. We show an altered proteomic signature in SMA already at early stages during MN differentiation, associated with ER to Golgi transport, mRNA splicing and protein ubiquitination, in line with known SMA phenotypes. These alterations in the SMA proteome increase further towards later stages of MN differentiation. In addition, we find differences in altered protein expression between SMA patients, which however, have similar biological functions. Finally, we highlight several known SMN-binding partners as well as proteins associated with ubiquitin-mediated proteolysis and evaluate their expression changes during MN differentiation. Altogether, our work provides a rich resource of molecular events during early stages of MN differentiation, containing potentially therapeutically interesting protein expression profiles for SMA.

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