scholarly journals The critical role of membralin in postnatal motor neuron survival and disease

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Bo Yang ◽  
Mingliang Qu ◽  
Rengang Wang ◽  
Jon E Chatterton ◽  
Xiao-Bo Liu ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Early Onset ◽  
Critical Role ◽  
Mutant Mice ◽  
Neuron Survival ◽  
Motor Neuron Survival ◽  
Selective Death

Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5–6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, is predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induces ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease.

scholarly journals Author response: The critical role of membralin in postnatal motor neuron survival and disease

2015 ◽  
Author(s):  
Bo Yang ◽  
Mingliang Qu ◽  
Rengang Wang ◽  
Jon E Chatterton ◽  
Xiao-Bo Liu ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Critical Role ◽  
Author Response ◽  
Neuron Survival ◽  
Motor Neuron Survival

Neonatal Death in Mice Lacking Cardiotrophin-like Cytokine is Associated with Multifocal Neuronal Hypoplasia

2008 ◽  
Vol 46 (3) ◽  
pp. 514-519 ◽  
Author(s):  
X. Zou ◽  
B. Bolon ◽  
J. K. Pretorius ◽  
C. Kurahara ◽  
J. McCabe ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Ventral Horn ◽  
Lumbar Spinal Cord ◽  
Facial Nucleus ◽  
In Ovo ◽  
Neuron Survival ◽  
Motor Neuron Survival ◽  
Lumbar Spinal

Mice with null mutations of ciliary neurotrophic factor (Cntf) receptor alpha (Cntf-Rα), or cytokine-like factor 1 (Clf), one component of Cntf-II (a heterodimeric Cntf-Rα ligand), die as neonates from motor neuron loss affecting the facial nucleus and ventral horn of the lumbar spinal cord. Exposure to cardiotrophin-like cytokine (Clc), the other putative Cntf-II element, supports motor neuron survival in vitro and in ovo. Confirmation that Clc ablation induces an equivalent phenotype to Clf deletion would support a role for Clc in the functional Cntf-II complex. In this study, Clc knockout mice had decreased facial motility, did not suckle, died within 24 hours, and had 32% and 29% fewer motor neurons in the facial nucleus and lumbar ventral horn, respectively; thus, Clc is essential for motor neuron survival during development. The concordance of the Clc knockout phenotype with those of mice lacking Cntf-Rα or Clf bolsters the hypothesis that Clc participates in Cntf-II.

scholarly journals Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase

1998 ◽  
Vol 95 (16) ◽  
pp. 9626-9630 ◽  
Author(s):  
Sébastien Couillard-Després ◽  
Qinzhang Zhu ◽  
Philip C. Wong ◽  
Donald L. Price ◽  
Don W. Cleveland ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Transgenic Mice ◽  
Protective Effect ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Spinal Root ◽  
Old Mice ◽  
H Protein

To investigate the role of neurofilaments in motor neuron disease caused by superoxide dismutase (SOD1) mutations, transgenic mice expressing a amyotrophic lateral sclerosis-linked SOD1 mutant (SOD1G37R) were mated with transgenic mice expressing human neurofilament heavy (NF-H) subunits. Unexpectedly, expression of human NF-H transgenes increased by up to 65%, the mean lifespan of SOD1G37R mice. Microscopic examination corroborated the protective effect of NF-H protein against SOD1 toxicity. Although massive neurodegeneration occurred in 1-yr-old mice expressing SOD1G37R alone, spinal root axons and motor neurons were remarkably spared in doubly SOD1G37R;NF-H-transgenic littermates.

scholarly journals Role of EphA4 in Mediating Motor Neuron Death in MND

2021 ◽  
Vol 22 (17) ◽  
pp. 9430
Author(s):  
Jing Zhao ◽  
Claire H. Stevens ◽  
Andrew W. Boyd ◽  
Lezanne Ooi ◽  
Perry F. Bartlett
Keyword(s):  
Cell Death ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Functional Outcomes ◽  
Underlying Mechanism ◽  
Neuron Death ◽  
Pathological Characteristics ◽  
Motor Neuron Death

Motor neuron disease (MND) comprises a group of fatal neurodegenerative diseases with no effective cure. As progressive motor neuron cell death is one of pathological characteristics of MND, molecules which protect these cells are attractive therapeutic targets. Accumulating evidence indicates that EphA4 activation is involved in MND pathogenesis, and inhibition of EphA4 improves functional outcomes. However, the underlying mechanism of EphA4’s function in MND is unclear. In this review, we first present results to demonstrate that EphA4 signalling acts directly on motor neurons to cause cell death. We then review the three most likely mechanisms underlying this effect.

scholarly journals ALS-Like Disorder in Three HIV-Positive Patients: Case Series

2021 ◽  
pp. 59-64
Author(s):  
Zachary Aaron Satin ◽  
Elham Bayat
Keyword(s):  
Antiretroviral Therapy ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Case Series ◽  
Retrospective Chart Review ◽  
Effective Control ◽  
Hiv Positive ◽  
Disease Course ◽  
Retroviral Infection

There appears to be a relationship between retroviruses such as HIV and the development of an ALS-like syndrome. Few cases have been reported; however, there exists evidence of a higher frequency of motor neuron disease in HIV-infected patients, as well as potential slowing and reversibility of disease course with combination antiretroviral therapy. We conducted a retrospective chart review of patients presenting to the George Washington University ALS Clinic from September 2006 to June 2018 to identify patients with HIV receiving HAART who were subsequently diagnosed with ALS or an ALS-like disorder. Our goals were to describe our patients’ disease course and compare them to general characteristics of ALS. We report three cases of HIV-positive individuals, all male, who were subsequently diagnosed with ALS. Each presented with symptoms of limb onset ALS with involvement of upper and lower motor neurons and whose disease originated at the cervical level. All three had been diagnosed with HIV prior to presentation and were presumably compliant with antiretroviral therapy throughout. Our patients demonstrated effective control of their HIV infection. Each experienced relatively slow progression of motor impairment compared to general ALS characteristics. Our study offers a distinct profile of HIV-positive patients compliant with HAART subsequently diagnosed with an ALS-like disorder. Further study should aim to uncover pathophysiological similarities between motor neuron disease both in the presence and absence of retroviral infection and to develop effective medical therapy for each.

scholarly journals LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

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