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Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS

ABSTRACT: Ubiquitous expression of ALS-causing mutations in superoxide dismutase 1 (SOD1) provoke non-cell autonomous paralytic disease. By combining ribosome affinity purification and high-throughput sequencing, a cascade of mutant SOD1-dependent, cell type-specific changes are now identified. Initial mutant-dependent damage is restricted to motor neurons and includes synapse and metabolic abnormalities, endoplasmic reticulum (ER) stress, and selective activation of the PERK arm of the unfolded protein response. PERK activation correlates with what we identify to be a naturally low level of ER chaperones in motor neurons. Early changes in astrocytes are to genes involved in inflammation and metabolism and that are targets of the PPAR and LXR transcription factors. Dysregulation of myelination and lipid signaling pathways and activation of ETS transcription factors occur in oligodendrocytes only after disease initiation. Thus, pathogenesis involves a temporal cascade of cell type selective damage initiating in motor neurons, with subsequent damage within glia driving disease propagation.

ORGANISM(S): Mus musculus

PROVIDER: GSE74724 | GEO | 2015/12/09

SECONDARY ACCESSION(S): PRJNA301347

REPOSITORIES: GEO

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Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS

Project description:Ubiquitous expression of ALS-causing mutations in superoxide dismutase 1 (SOD1) provoke non-cell autonomous paralytic disease. By combining ribosome affinity purification and high-throughput sequencing, a cascade of mutant SOD1-dependent, cell type-specific changes are now identified. Initial mutant-dependent damage is restricted to motor neurons and includes synapse and metabolic abnormalities, endoplasmic reticulum (ER) stress, and selective activation of the PERK arm of the unfolded protein response. PERK activation correlates with what we identify to be a naturally low level of ER chaperones in motor neurons. Early changes in astrocytes are to genes involved in inflammation and metabolism and that are targets of the PPAR and LXR transcription factors. Dysregulation of myelination and lipid signaling pathways and activation of ETS transcription factors occur in oligodendrocytes only after disease initiation. Thus, pathogenesis involves a temporal cascade of cell type selective damage initiating in motor neurons, with subsequent damage within glia driving disease propagation. Cell type-specific mRNA was purified by ribosome affinity purification from the spinal cord of bacTRAP reporter mice that label selective cell types by EGFP-tagged ribosome RPL10A. Sequencing libraries were prepared from 3-6 biological replicates for each genotype to determine the mutant induced gene expression changes in specific cell types.

2015-12-09 | E-GEOD-74724 | biostudies-arrayexpress

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

PERK is a critical metabolic hub for immunosuppressive function in macrophages

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Pathways Disrupted in Human ALS Motor Neurons Identified Through Genetic Correction of Mutant SOD1

Project description:Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neural degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered sub-cellular transport as well as activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that perturbations in these pathways were indeed the source of altered transcript levels. 5 samples, 2 patient-derived SOD1A4V and 3 isogenic control samples where the mutation has been corrected. All samples are motor neurons derived from induced pluripotent stem cells (iPSCs), and isolated after lentiviral infection with an Hb9:RFP construct and FACS purification. Each sample is a separate biological replicate.

2014-02-03 | E-GEOD-54409 | biostudies-arrayexpress

Selective Death in Spinal Muscular Atrophy: Genome-Wide RNA-Seq Using Purified Patient-Derived Motor Neurons

Project description:Spinal Muscular Atrophy (SMA) is well-known to be caused by mutations in the gene Survival of Motor Neuron 1 (SMN1). Because this gene is ubiquitously expressed, it remains poorly understood why motor neurons (MNs) are one of the most affected cell types. To begin to address this question, we carried out RNA-sequencing studies using fixed, antibody-labeled and purified MNs produced from control and SMA patient-derived induced pluripotent stem cells (iPSCs). We found SMA-specific changes in MNs, including hyper-activation of the endoplasmic reticulum (ER) stress pathway and enhanced apoptosis. Functional studies demonstrated that inhibition of ER stress improves overall MN health and survival in vitro even in MNs with low SMN levels. In SMA mice, we show that systemic delivery of an ER stress inhibitor that crosses the blood-brain-barrier led to preservation of MNs in the spinal cord and prolonged survival of these mice. Therefore, our study implies that selective activation of ER stress underlies MN death in SMA. Moreover, the approach we have taken would be broadly applicable to studying disease-prone human cells in heterogeneous cultures. total RNA collected from ES cell and patient ES cell derived spinal motor neurons

2015-09-01 | E-GEOD-69175 | biostudies-arrayexpress

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

2014-12-17 | GSE49023 | GEO

Pathways Disrupted in Human ALS Motor Neurons Identified Through Genetic Correction of Mutant SOD1

2014-02-03 | GSE54409 | GEO

Microarray analysis identifies the gene signature of surviving motor neurons in human SOD1-related motor neuron disease

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Post-translational modification analysis of VDAC1 in ALS-SOD1 model cells reveals specific asparagine and glutamine deamination

Project description:Mitochondria from affected tissues of Amyotrophic Lateral Sclerosis (ALS) patients show morphological and biochemical abnormalities. The impairment of mitochondrial functions causes oxidative damage and accumulation of ROS and represents one of the major features that lead to the selective death of motor neurons in ALS. Our aim was to assess the ability of oxidative stress found in ALS to induce post-translational modifications (PTMs) in VDAC1, the main protein of the outer mitochondrial membrane and known to interact with SOD1 mutants related to ALS. In this work, specific post-translational modifications (PTMs) of the VDAC1 protein purified by hydroxyapatite from mitochondria of a NSC34 cell line expressing human SOD1G93A, a suitable ALS motor neurons model, were analyzed by tryptic and chymotryptic proteolysis and UHPLC/High Resolution ESI-MS/MS. Selective deamidations of asparagine and glutamine of VDAC1 in ALS-related NSC34-SOD1G93A cells but not in NSC34-SOD1 or NSC34wt cells were found. In addition, we identified differences in the over-oxidation of methionine and cysteines between VDAC1 purified from ALS model or non-ALS NSC34 cells. The specific range of PTMs identified exclusively in VDAC1 from NSC34-SOD1G93A cells but not fromNSC34control lines, suggests the appearance of important changes to the structure of the VDAC1 channel and therefore to the bioenergetics metabolism of ALS motor neurons.

2020-12-10 | PXD022598 | Pride

PERK is a critical metabolic hub for immunosuppressive function in macrophages

Project description:Here we report that the Th2 cytokine IL-4 and the tumor microenvironment activated protein kinase RNA-like ER kinase (PERK) stress signaling cascade to promote immunosuppressive M2 activation and proliferation. PERK activation mediated the upregulation of PSAT1 and serine biosynthesis via the downstream transcription factor ATF4. We found that Increased serine biosynthesis could result in enhanced mitochondrial function and α-ketoglutarate (α-KG) production required for JMJD3-dependent epigenetic modification.

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