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

Jiang, LuLin; Zhu, Bing; Zhao, Yingjun; Li, Xiaoguang; Liu, Tongfei; Piña‐Crespo, Juan C.; Zhou, Lisa; Wei, Xu; Rodrí­guez, Marí­a José; Yu, Haiyang; Cleveland, Don W.; Ravits, John; Cruz, Sandrine Da; Long, Tao; Zhang, Dongxian; Huang, Timothy; Xu, Huaxi

doi:10.1172/jci127695

Cited by 34 publications

(31 citation statements)

References 68 publications

(87 reference statements)

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“…Among the RNF185/MBRL complex components, MBRL is the one with the highest number of transmembrane segments (6–8 predicted). Although its function is unknown, ablation of MBRL in mice is perinatally lethal ( Jiang et al., 2019 ; Yang et al., 2015 ). Curiously, re-expression of MBRL specifically in astrocytes is sufficient to rescue the lethality in the KO animals, highlighting the essential function of MBRL in the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

“…Curiously, re-expression of MBRL specifically in astrocytes is sufficient to rescue the lethality in the KO animals, highlighting the essential function of MBRL in the central nervous system. Amyotrophic lateral sclerosis mouse models and patient spinal cord samples showed decreased MBRL expression, suggesting that its function may be related to the etiology of this neurodegenerative disease ( Jiang et al., 2019 ). Understanding how loss of MBRL in the ER gives rise to these phenotypes is of paramount importance.…”

Section: Discussionmentioning

confidence: 99%

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Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex

et al. 2020

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Summary Misfolded proteins in the endoplasmic reticulum (ER) are degraded by ER-associated degradation (ERAD). Although ERAD components involved in degradation of luminal substrates are well characterized, much less is known about quality control of membrane proteins. Here, we analyzed the degradation pathways of two short-lived ER membrane model proteins in mammalian cells. Using a CRISPR-Cas9 genome-wide library screen, we identified an ERAD branch required for quality control of a subset of membrane proteins. Using biochemical and mass spectrometry approaches, we showed that this ERAD branch is defined by an ER membrane complex consisting of the ubiquitin ligase RNF185, the ubiquitin-like domain containing proteins TMUB1/2 and TMEM259/Membralin, a poorly characterized protein. This complex cooperates with cytosolic ubiquitin ligase UBE3C and p97 ATPase in degrading their membrane substrates. Our data reveal that ERAD branches have remarkable specificity for their membrane substrates, suggesting that multiple, perhaps combinatorial, determinants are involved in substrate selection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex

et al. 2020

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“…mouse models and its deletion suppresses EAAT2 expression through a TNF-α/TNF receptor 1/nuclear factor κ-B pathway. Overexpression of membralin in astrocytes was shown to increase EAAT2 expression and improve motor neuron survival (Jiang et al, 2019).…”

Section: A Brief History Of Als: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

Armada‐Moreira

Gomes

Pina

et al. 2020

Front. Cell. Neurosci.

180

128

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Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated

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“…Although the pathogenesis of ALS is extremely intricate and remains largely unknown, inflammation and oxidative stress play a pivotal role in ALS pathogenesis and contribute to the vicious cycle of neurodegeneration in the lumbar spinal cord. There is growing evidence that activated microglia and reactive astrocytes increase in the spinal cord of ALS patients [4] and model mice [5]. Activation of glial cells in ALS is marked by the elevated production of neurotoxic mediators such as reactive oxygen species (ROS), proinflammatory cytokines, and inflammatory mediators [6].…”

Section: Introductionmentioning

confidence: 99%

“…Neuroinflammation is the activation of an immune response in the central nervous system by activated astrocytes and microglial cells. Activation of astrocytes and microglia is prominently observed in regions of degenerating motor neurons in ALS patients as well as in model mice [4,5,37,38]. A previous study conducted in our laboratory showed that the levels of spinal GFAP and Iba-1 expression were elevated in an age-dependent manner in G93A mice [17].…”

mentioning

confidence: 99%

Bidens pilosa Extract Administered after Symptom Onset Attenuates Glial Activation, Improves Motor Performance, and Prolongs Survival in a Mouse Model of Amyotrophic Lateral Sclerosis

Kosuge

Kaneko

Nango

et al. 2020

Oxidative Medicine and Cellular Longevity

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Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by progressive paralysis resulting from the death of upper and lower motor neurons. There is currently no effective pharmacological treatment for ALS, and the two approved drugs riluzole and edaravone have limited effects on the symptoms and only slightly prolong the life of patients. Therefore, the development of effective therapeutic strategies is of paramount importance. In this study, we investigated whether Miyako Island Bidens pilosa (MBP) can alleviate the neurological deterioration observed in a superoxide dismutase-1 G93A mutant transgenic mouse (G93A mouse) model of ALS. We orally administered 2 g/kg/day of MBP to G93A mice at the onset of symptoms of neurodegeneration (15 weeks old) until death. Treatment with MBP markedly prolonged the life of ALS model mice by approximately 20 days compared to that of vehicle-treated ALS model mice and significantly improved motor performance. MBP treatment prevented the reduction in SMI32 expression, a neuronal marker protein, and attenuated astrocyte (detected by GFAP) and microglia (detected by Iba-1) activation in the spinal cord of G93A mice at the end stage of the disease (18 weeks old). Our results indicate that MBP administered after the onset of ALS symptoms suppressed the inflammatory activation of microglia and astrocytes in the spinal cord of the G93A ALS model mice, thus improving their quality of life. MBP may be a potential therapeutic agent for ALS.

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

Cited by 34 publications

References 68 publications

Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex

Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

Bidens pilosa Extract Administered after Symptom Onset Attenuates Glial Activation, Improves Motor Performance, and Prolongs Survival in a Mouse Model of Amyotrophic Lateral Sclerosis

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