期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 8, 页码 3103-3120出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI127695
关键词
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资金
- NIH [R01 AG061875, R21 AG059217, R01 AG038710, R01 AG044420, R01 NS046673, R01 AG056130, R01 AG056114, R01 NS27036]
- Tanz Family Fund
- Cure Alzheimer's Fund
- Sanford Burnham Prebys Animal Resources Core
- Histology Core
- Cancer Metabolism Core
- Genomics Core
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 indicated 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 show that activation of the TNF receptor (TNFR1) NF kappa B 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 SOD1(G93A) astrocytes decreased TNFR1 levels and increased EAAT2 expression, and improved motor neuron survival. Importantly, upregulation of membralin in SOD1(G93A) mice significantly prolonged mouse survival. Our study provided a mechanism for ALS pathogenesis where membralin limited glutamatergic neurotoxicity, suggesting that modulating membralin had potential in ALS therapy.
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