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| Status |
Public on May 07, 2019 |
| Title |
Membralin deficiency dysregulates astrocytic glutamate homeostasis leading to ALS-like impairment |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are yet unclear. Specific deletion of the ER-component membralin in astrocytes manifested postnatal motor defects and lethality in mice, causing the accumulation of extracellular glutamate through reducing the glutamate transporter EAAT2. Restoring EAAT2 levels in membralin KO astrocytes limited astrocyte-dependent excitotoxicity in motor neurons. Transcriptomic profiles from mouse astrocytic membralin KO motor cortex indicateed significant perturbation in KEGG pathway components related to ALS, including downregulation of Eaat2 and upregulation of Tnfrsf1a. Changes in gene expression with membralin deletion also overlapped with mouse ALS models and reactive astrocytes. Our results shown that activation of TNF receptor (TNFR1)-NFkB pathway known to suppress Eaat2 transcription was upregulated with membralin deletion. Further, reduced membralin and EAAT2 levels correlated with disease progression in spinal cord from SOD1-mutant mouse models, and reductions in membralin/EAAT2 were observed in human ALS spinal cord. Importantly, overexpression of membralin in SOD1G93A astrocytes decreased TNFR1 levels and increased EAAT2 expression, and improved motor neuron survival. Importantly, upregulation of membralin in SOD1G93A mice significantly prolonged mouse survival. Together, our study provides a mechanism for ALS pathogenesis where membralin limits glutamatergic neurotoxicity, suggesting that modulating membralin has potential in ALS therapy
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| Overall design |
Motor cortex mRNA profiles from 22-day old wild type (WT) and membralin astrocyte conditional knockout (Astro-mem KO) were generated by RNAseq. Five biological repeats were included per genotype.
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| Contributor(s) |
Jiang L, Xu H |
| Citation(s) |
31112137 |
| Submission date |
May 06, 2019 |
| Last update date |
Aug 06, 2019 |
| Contact name |
Timothy Huang |
| E-mail(s) |
thuang@sbpdiscovery.org
|
| Phone |
858-646-3100
|
| Organization name |
Sanford Burnham Prebys Medical Discovery Institute
|
| Lab |
Huang/Xu Lab
|
| Street address |
10901 N Torrey Pines Rd.
|
| City |
La Jolla |
| State/province |
CA |
| ZIP/Postal code |
92037 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA541312 |
| SRA |
SRP195618 |
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