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Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. While the contribution of peripheral organs remains incompletely understood, recent evidence suggests that brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) could play a role in diseased context as ALS. In this study, we employed a multi-omics approach, including RNA sequencing and proteomics, to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed significant changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting ALS-related features such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content, which negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS, contributing to skeletal muscle degeneration through the secretion of dysfunctional EVs. This study provides novel insights into the role of BAT in ALS pathogenesis and highlights potential therapeutic targets for mitigating muscle wasting in ALS patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE273052 | GEO | 2024/08/05

REPOSITORIES: GEO

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Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis.

Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. While the contribution of peripheral organs remains incompletely understood, recent evidence suggests that brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) could play a role in diseased context as ALS. In this study, we employed a multi-omics approach, including RNA sequencing and proteomics, to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed significant changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting ALS-related features such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content, which negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS, contributing to skeletal muscle degeneration through the secretion of dysfunctional EVs. This study provides novel insights into the role of BAT in ALS pathogenesis and highlights potential therapeutic targets for mitigating muscle wasting in ALS patients.

2025-02-03 | PXD054147 | Pride

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

Expression data from mutant SOD1(G93A) transgenic mice

2009-10-17 | GSE18597 | GEO

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

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

2014-03-04 | E-GEOD-55507 | biostudies-arrayexpress

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

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

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

Cortical glia in SOD1(G93A) mice are subtly affected by ALS-like pathology

Project description:The role of glia in amyotrophic lateral sclerosis (ALS) is undeniable. Their disease-related activity has been extensively studied in the spinal cord, but only partly in the brain. We present herein a comprehensive study of glia in the motor cortex of SOD1(G93A) mice – a widely used model of ALS. Using single-cell RNA sequencing (scRNA-seq) and immunohistochemistry, we inspected astrocytes, microglia and oligodendrocytes, in four stages of the disease, respecting the factor of sex. We report insignificant motor neuron loss in the cortex, and likewise, minimal changes of glia throughout the disease progression and regardless of sex. Pseudobulk and single-cell analyses revealed subtle disease-related transcriptional alterations at the end-stage in microglia and oligodendrocytes, which were supported by immunohistochemistry. Therefore, our data conclusively prove that the SOD1(G93A) mouse motor cortex does not recapitulate the disease in patients, and we recommend the use of a different model for future studies of the cortical ALS pathology.

2023-04-21 | GSE206330 | GEO

Perturbations of the proteome in primary astrocytes from the hSOD1(G93A) ALS mouse model

Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose pathophysiology is largely unknown. Despite motor neuron death is recognized as the key event in ALS, astrocytes dysfunctionalities and neuroinflammation were demonstrated to accompany and probably even drive motor neuron loss. Nevertheless, the mechanisms priming astrocyte failure and hyperactivation are still obscure. In this work, altered pathways in ALS astrocytes were unveiled by investigating the proteomic profile of primary spinal-cord astrocytes derived from transgenic ALS mouse model overexpressing the human (h)SOD1(G93A) protein, in comparison with the transgenic counterpart expressing hSOD1(WT) protein. In this research, we showed that hSOD1(G93A) astrocytes present a profound alterations in the expression of proteins involved in proteostasis and glutathione metabolism.

2022-02-17 | PXD026576 | Pride

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

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