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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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MiRNA expression in fast and slow skeletal muscle of wild type and SOD1-G93A mice

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disease that progressively debilitates neuronal cells that control voluntary muscle activity. In a mouse model of ALS that expresses mutated human superoxide dismutase 1 (SOD1-G93A) skeletal muscle is one of the tissues affected early by mutant SOD1 toxicity. Fast-twitch and slow-twitch muscles are differentially affected in ALS patients and in the SOD1-G93A model, fast-twitch muscles being more vulnerable. We used miRNA microarrays to investigate miRNA alterations in fast-twitch (EDL) and slow-twitch (soleus) skeletal muscles of symptomatic SOD1-G93A animals and their age-matched wild type littermates. At age of 90 days RNA was extracted from extensor digitorum longus (EDL) and soleus (SOL) muscles of male SOD1-G93A animals and their age-matched wild type male littermates. RNA was hybridized on Affymetrix Multispecies miRNA-2_0 Array.

ORGANISM(S): Mus musculus

SUBMITTER: Janne Toivonen

PROVIDER: E-GEOD-55507 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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MicroRNA-206: a potential circulating biomarker candidate for amyotrophic lateral sclerosis.

Toivonen Janne M JM Manzano Raquel R Oliván Sara S Zaragoza Pilar P García-Redondo Alberto A Osta Rosario R

PloS one 20140220 2

Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disease that progressively debilitates neuronal cells that control voluntary muscle activity. Biomarkers are urgently needed to facilitate ALS diagnosis and prognosis, and as indicators of therapeutic response in clinical trials. microRNAs (miRNAs), small posttranscriptional modifiers of gene expression, are frequently altered in disease conditions. Besides their important regulatory role in variety of biological processes, miRNAs can ...[more]

PMID: 24586506

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miRNA expression in fast and slow skeletal muscle of wild type and SOD1-G93A mice

Project description:Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disease that progressively debilitates neuronal cells that control voluntary muscle activity. In a mouse model of ALS that expresses mutated human superoxide dismutase 1 (SOD1-G93A) skeletal muscle is one of the tissues affected early by mutant SOD1 toxicity. Fast-twitch and slow-twitch muscles are differentially affected in ALS patients and in the SOD1-G93A model, fast-twitch muscles being more vulnerable. We used miRNA microarrays to investigate miRNA alterations in fast-twitch (EDL) and slow-twitch (soleus) skeletal muscles of symptomatic SOD1-G93A animals and their age-matched wild type littermates.

2014-03-04 | GSE55507 | GEO

Proteomic Profiling of Brain and Medullar Reveals the Dysregulation of Myosin Complex and Striated Muscle Contraction Pathway in ALS mouse model

Project description:In this study, we used this strategy to reveal the proteome changes of cerebral cortex, hippocampus and medulla of SOD1*G93A mice. Hundreds of changed proteins and many of important biological process were found in the ALS mouse brain.

2019-03-21 | PXD010553 | Pride

Transcription profiling of mouse motorneurons during progression of the disease in transgenic SOD1(G93A) mice that develop motorneuron loss

Project description:To identify candidate genes that may be involved in motoneuron degeneration, we combined laser capture microdissection with microarray technology. Gene expression in motoneurons was analyzed during the progression of the disease in transgenic SOD1(G93A) mice that develop motoneuron loss. Three major observations were made : first, there was only a small number of genes that were differentially expressed in motoneurons at a pre-symptomatic age (27 out of 34,000 transcripts). Secondly, there is an early specific up-regulation of the gene coding for the intermediate filament vimentin that is increased even further during disease progression. Using in situ hybridization and immunohistochemical analysis, we show that vimentin expression was not only elevated in motoneurons but that the protein formed inclusions in the motoneuron cytoplasm. Thirdly, a time-course analysis of the motoneurons at a symptomatic age (90 and 120 days) showed a modest de-regulation of only a few genes associated with cell death pathways; however, a massive up-regulation of genes involved in cell growth and/or maintenance was observed. This is the first description of the gene profile of SOD1(G93A) motoneurons during disease progression and unexpectedly, no widespread induction of cell death-associated genes was detected in motoneurons of SOD1(G93A) mice.

2005-10-30 | E-MEXP-453 | biostudies-arrayexpress

Kir4.1-dependent astrocyte-fast motor neuron interactions are required for peak strength

Project description:Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast α-motor neurons (FαMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report that ventral horn astrocytes express the inward rectifying K+ channel Kir4.1 (aka, Kcnj10) around MNs in a VGLUT1-dependent manner. Loss-of astrocyte-encoded Kir4.1 selectively altered FαMN size, function and led to reduced peak strength. Overexpression of Kir4.1 in astrocytes was sufficient to increase MN size through activation of the PI3K/mTOR/pS6 pathway. Kir4.1 was downregulated cell-autonomously in astrocytes derived from amyotrophic lateral sclerosis (ALS) patients with SOD1 mutation. However, astrocyte Kir4.1 was dispensable for FαMN survival even in the mutant SOD1 background. These findings show that astrocyte Kir4.1 is essential for maintenance of peak strength and suggest that Kir4.1 downregulation uncouples symptoms of muscle weakness from MN cell death in ALS.

2018-05-01 | GSE111148 | GEO

Expression data from mutant SOD1(G93A) transgenic mice

2009-10-17 | GSE18597 | GEO

Expression data from mutant SOD1(G93A) transgenic mice

Project description:Expression profiling of spinal cord from SOD1(G93A) mice and age matched controls at ages 28, 42, 56, 70,98,112, and 126 days of age. We used microarrays to determine differential gene expression throughout disease progression in the spinal cord of mutant SOD1(G93A) model of ALS. Samples were collected from male B6SJL SOD1(G93A) and age matched controls. 3 samples were collected representing each genotype and age group for RNA extraction and hybridization on Affymetrix microarrays.

2009-10-17 | E-GEOD-18597 | biostudies-arrayexpress

Mouse ES-derived motor neurons (ES-MN) exposed to SOD1 mutant mouse astrocyte conditioned media

Project description:This datased was used to obtain a genome-wide expression signature for the early response of mouse motor neurons to mutant SOD1 astrocytes conditioned media. Neurons, far from living in isolation, are surrounded by a host of other neuronal and non-neuronal cells, such as astrocytes. The latter entertain complex functional interactions with neighboring neurons, which, under normal conditions, are important for the their well-being. In pathological situations, however, altered astrocyte behavior may contribute to the demise of neighboring neurons. Such non-cell autonomous pathogenic scenario is increasingly considered in a variety of disorders, including amyotrophic lateral sclerosis (ALS), the most frequent adult-onset paralytic disorder. Assembly and interrogation of gene regulatory models has helped elucidate causal mechanisms responsible for the presentation of several tumor-related phenotypes. To systematically elucidate the effectors of neurodegeneration in a model of ALS, we first developed techniques for the efficient purification of motor neurons (MNs), the primary target of ALS neurodegenerative process. We then generated gene expression profiles to fully characterize the critical timepoints associated with initiation and commitment of MN degenerative progression in an in vitro murine mutant SOD1 (mSOD1) model of ALS. ES cells were derived from transgenic Hlxb9-GFP1Tmj mice expressing eGFP and CD2 driven by the mouse HB9 promoter. These cells were then differentiated into motor neurons (ES-MN) as described previously [PMID 12176325] ES-MN were exposed to non-transgenic (NTg), G93A mutant SOD1 (mSOD1) or wtSOD1 over-expression astrocytes conditioned media for 0 days (time zero control), 1 day, and 3 days. Total RNA was extracted and profiled by RNAseq.

2014-12-17 | E-GEOD-49023 | biostudies-arrayexpress

Transcription profiling of mouse laser capture microdissected SOD1 G93A motor neurons reveals cellular pathways involved in the adaptation and progression of motor neuron injury in the mouse model of familial ALS

Project description:Microarray analysis has been applied to the study of ALS in order to investigate gene expression in whole spinal cord homogenates of SOD1 G93A mice and human ALS cases, although the massive presence of glial cells and inflammatory factors has made it difficult to define which gene expression changes were motor neuron specific. Recently, laser capture microdissection (LCM), combined with microarray analysis, has allowed the identification of motor neuron specific changes in gene expression in human ALS cases. The aim of the present study is to combine LCM and microarray analysis to study how motor neurons in the spinal cord of transgenic SOD1 G93A mice and transgenic SOD1 WT respond to stimuli determined by the presence of the human mutant protein throughout the evolution of the stages in motor neuron injury Experiment Overall Design: Motor neurons have been isolated from the spinal cord of G93A mice and non transgenic littermates at different time points and the transcription expression profile of the isolated motor neurons has been analysed

2008-06-11 | E-GEOD-10953 | biostudies-arrayexpress

MiR-129-5p downregulates HuD expression impairing neuritogenesis in Amyotrophic Lateral Sclerosis

Project description:Amyotrophic lateral sclerosis (ALS) involves the degeneration of brain and spinal cord motor neurons. Mutations in Superoxide Dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and Fused-in-Sarcoma (FUS) account for 20-30 % of the familial ALS (fALS) cases. The RNA-binding proteins TDP-43 and FUS function in mRNA and miRNA biogenesis. MiRNAs are required for survival of neurons and deregulation of miRNA expression has been reported in several neurodegenerative disorders. Here, we report the dysregulation of DROSHA, DGCR8, and DICER in human neuroblastoma SH-SY5Y cells expressing the ALS-associated SOD1(G93A) mutant protein. MiRNA profiling in SH-SY5Y/SOD1(G93A) cells and transgenic SOD1(G93A) mice revealed upregulation of miR-129-5p at the early stage of disease. Moreover, miR-129-5p is also upregulated in lymphocytes of sporadic ALS patients. We demonstrate that miR-129-5p targets ELAVL4/HuD mRNA by binding to its 3’ UTR, which reduces HuD expression and impairs differentiation and neurite outgrowth. Conversely, treatment with an antagomir or complementation with HuD protein restores neuritogenesis. Collectively, our study identifies miR-129-5p and HuD as key regulators of neuronal differentiation and as potential therapeutic targets for ALS.

2018-02-01 | GSE94379 | GEO

CNS-derived extracellular vesicles from superoxide dismutase 1 (SOD1)G93A ALS mice originate from astrocytes and neurons and carry misfolded SOD1

Project description:Extracellular vesicles (EVs) are secreted by myriad cells in culture and also by unicellular organisms, and their identification in mammalian fluids suggests that EV release also occurs at the organism level. However, although it is clearly important to better understand EVs' roles in organismal biology, EVs in solid tissues have received little attention. Here, we modified a protocol for EV isolation from primary neural cell culture to collect EVs from frozen whole murine and human neural tissues by serial centrifugation and purification on a sucrose gradient. Quantitative proteomics comparing brain-derived EVs from nontransgenic (NTg) and a transgenic amyotrophic lateral sclerosis (ALS) mouse model, superoxide dismutase 1 (SOD1) G93A , revealed that these EVs contain canonical exosomal markers and are enriched in synaptic and RNA-binding proteins. The compiled brain EV proteome contained numerous proteins implicated in ALS, and EVs from SOD1 G93A mice were significantly depleted in myelin-oligodendrocyte glycoprotein compared with those from NTg animals. We observed that brain- and spinal cord–derived EVs, from NTg and SOD1 G93A mice, are positive for the astrocyte marker GLAST and the synaptic marker SNAP25, whereas CD11b, a microglial marker, was largely absent. EVs from brains and spinal cords of the SOD1 G93A ALS mouse model, as well as from human SOD1 familial ALS patient spinal cord, contained abundant misfolded and nonnative disulfide-cross-linked aggregated SOD1. Our results indicate that CNS-derived EVs from an ALS animal model contain pathogenic disease-causing proteins and suggest that brain astrocytes and neurons, but not microglia, are the main EV source.

2020-09-11 | PXD021396 | Pride

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