Journal Article

Membralin deficiency dysregulates astrocytic glutamate homeostasis, leading to ALS-like impairment

Zhu, Bing, Yu, Haiyang, Zhou, Lisa, Da Cruz, Sandrine, Zhang, Dongxian, Ravits, John, Pina-Crespo, Juan, Cleveland, Don W., Long, Tao, Huang, Timothy Y., Jiang, Lu-Lin, Zhao, Yingjun, Li, Xiaoguang, Xu, Wenxi, Rodriguez, Maria J., Liu, Tongfei, Xu, Huaxi

2019

Overview

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 shown that activation of TNF receptor (TNFR1)-NFκB 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 provided a mechanism for ALS pathogenesis where membralin limited glutamatergic neurotoxicity, suggesting that modulating membralin had potentials in ALS therapy.

• Publisher: American Society for Clinical Investigation
• Subject: Alzheimer's disease / Amino acids / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Analysis / Animal models / Animals / Astrocytes / Astrocytes - metabolism / Astrocytes - pathology / Biochemistry / Bioinformatics / Biomedical research / Cortex (motor) / Defects / Degeneration / Development and progression / Down-Regulation / Excitatory Amino Acid Transporter 2 - biosynthesis / Excitatory Amino Acid Transporter 2 - genetics / Excitotoxicity / Gene deletion / Gene expression / Genes / Genetic aspects / Glutamate / Glutamatergic transmission / Glutamic Acid - genetics / Glutamic Acid - metabolism / Glutamic acid transporter / Homeostasis / Humans / Lethality / Mice / Mice, Knockout / Motor Cortex - metabolism / Motor Cortex - pathology / Motor neurons / Nerve Tissue Proteins - deficiency / Nerve Tissue Proteins - metabolism / Nervous system / Neurodegeneration / Neurons / Neurotoxicity / NF-κB protein / Pathogenesis / Pathology / Physiology / Receptors, Tumor Necrosis Factor, Type I - biosynthesis / Receptors, Tumor Necrosis Factor, Type I - genetics / Spinal cord / Superoxide dismutase / Superoxide Dismutase - biosynthesis / Superoxide Dismutase - genetics / Transcription / Transcription, Genetic / Tumor necrosis factor receptors / Up-Regulation