The Motor Neuron Degeneration (mnd) Gene Acts Intrinsically in Motor Neurons and Peripheral Fibroblasts

1997 ◽  
Vol 9 (3) ◽  
pp. 185-193 ◽  
Author(s):  
Joanne C. Porter ◽  
Anne Messer ◽  
Alan Peterson
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration

scholarly journals Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liuji Chen ◽  
Ren Na ◽  
Kirsten Danae McLane ◽  
Cody Sylvester Thompson ◽  
Ju Gao ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Transgenic Mice ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Disease Onset ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Sporadic Als

AbstractDegeneration and death of motor neurons in Amyotrophic Lateral Sclerosis (ALS) are associated with increased lipid peroxidation. Lipid peroxidation is the driver of ferroptosis, an iron-dependent oxidative mode of cell death. However, the importance of ferroptosis in motor neuron degeneration of ALS remains unclear. Glutathione peroxidase 4 (Gpx4) is a key enzyme in suppressing ferroptosis by reducing phospholipid hydroperoxides in membranes. To assess the effect of increased protection against ferroptosis on motor neuron disease, we generated SOD1G93AGPX4 double transgenic mice by cross-breeding GPX4 transgenic mice with SOD1G93A mice, a widely used ALS mouse model. Compared with control SOD1G93A mice, both male and female SOD1G93AGPX4 mice had extended lifespans. SOD1G93AGPX4 mice also showed delayed disease onset and increased motor function, which were correlated with ameliorated spinal motor neuron degeneration and reduced lipid peroxidation. Moreover, cell toxicity induced by SOD1G93A was ameliorated by Gpx4 overexpression and by chemical inhibitors of ferroptosis in vitro. We further found that the anti-ferroptosis defense system in spinal cord tissues of symptomatic SOD1G93A mice and sporadic ALS patients might be compromised due to deficiency of Gpx4. Thus, our results suggest that ferroptosis plays a key role in motor neuron degeneration of ALS.

scholarly journals PAK4 Suppresses Motor Neuron Degeneration in hSOD1G93A -Linked ALS Cell and Rat Models

2020 ◽  
Author(s):  
Chaohua Cong ◽  
Weiwei Liang ◽  
Chunting Zhang ◽  
Ying Wang ◽  
Yueqing Yang ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Western Blotting ◽  
Motor Neurons ◽  
Neuroprotective Effect ◽  
Tunel Staining ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
In Vivo Models ◽  
Creb Pathway

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. The exact mechanisms underlying motor neuron death in ALS are still not fully understood, but a growing body of evidence indicates that inflammatory could accentuate disease severity and accelerate disease progression. Currently, no neuroprotective strategies have effectively prevented the progression of this disease.Methods: IF, western blotting and RT-PCR were used to analyze the expression of PAK4 in vitro and in vivo models of ALS. We examined PAK4 function in ALS and the underlying mechanism by cell transfection, intraspinally injection of LV-PAK4 in hSOD1G93A mice, flow cytometry, TUNEL staining, IF and western blotting.Results: Here, we observed that the expression and activity of PAK4 significantly decreased in hSOD1G93A-related cell and mouse models of ALS. In hSOD1G93A mice，the expression of PAK4 began to decrease at early-symptom stages of the disease. PAK4 silencing increased degeneration of motor neurons (NSC34 cells) and suppressed the CREB pathway. Overexpression of PAK4 protected motor neurons from hSOD1G93A-induced degeneration by increasing the levels and transcriptional activity of CREB. The neuroprotective effect of PAK4 was markedly inhibited by compound 3i, a specific CREB inhibitor. In hSOD1G93A-linked cell and mice, the CREB pathway, as the downstream target of decreased PAK4, was inhibited, and cell apoptosis increased. We also found that the expression of PAK4 was negatively regulated by miR-9-5p, and the miR-9-5p levels were upregulated in ALS. In vivo experiments revealed that PAK4 overexpression in the spinal neurons of hSOD1G93A mice suppressed motor neuron degeneration, prolonged survival and promoted the CREB pathway. Conclusion: These results indicate that PAK4 plays a protective role for motor neurons by targeting CREB, suggesting it may be a useful therapeutic target in ALS.

scholarly journals A microfluidic approach to rescue ALS motor neuron degeneration using rapamycin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Phaneendra Chennampally ◽  
Ambreen Sayed-Zahid ◽  
Prabakaran Soundararajan ◽  
Jocelyn Sharp ◽  
Gregory A. Cox ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Embryonic Stem ◽  
Immunosuppressive Drug ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Lateral Sclerosis

AbstractTAR DNA-binding protein-43 (TDP-43) is known to accumulate in ubiquitinated inclusions of amyotrophic lateral sclerosis affected motor neurons, resulting in motor neuron degeneration, loss of motor functions, and eventually death. Rapamycin, an mTOR inhibitor and a commonly used immunosuppressive drug, has been shown to increase the survivability of Amyotrophic Lateral Sclerosis (ALS) affected motor neurons. Here we present a transgenic, TDP-43-A315T, mouse model expressing an ALS phenotype and demonstrate the presence of ubiquitinated cytoplasmic TDP-43 aggregates with > 80% cell death by 28 days post differentiation in vitro. Embryonic stem cells from this mouse model were used to study the onset, progression, and therapeutic remediation of TDP-43 aggregates using a novel microfluidic rapamycin concentration gradient generator. Results using a microfluidic device show that ALS affected motor neuron survival can be increased by 40.44% in a rapamycin dosage range between 0.4-1.0 µM.

scholarly journals Sonic Hedgehog-Gli1 Signaling and Cellular Retinoic Acid Binding Protein 1 Gene Regulation in Motor Neuron Differentiation and Diseases

2020 ◽  
Vol 21 (11) ◽  
pp. 4125
Author(s):  
Yu-Lung Lin ◽  
Yi-Wei Lin ◽  
Jennifer Nhieu ◽  
Xiaoyin Zhang ◽  
Li-Na Wei
Keyword(s):  
Retinoic Acid ◽  
Motor Neuron ◽  
Sonic Hedgehog ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Minimal Promoter ◽  
Expression Data ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Acid Binding Protein

Cellular retinoic acid-binding protein 1 (CRABP1) is highly expressed in motor neurons. Degenerated motor neuron-like MN1 cells are engineered by introducing SODG93A or AR-65Q to model degenerated amyotrophic lateral sclerosis (ALS) or spinal bulbar muscular atrophy neurons. Retinoic acid (RA)/sonic hedgehog (Shh)-induced embryonic stem cells differentiation into motor neurons are employed to study up-regulation of Crabp1 by Shh. In SODG93A or AR-65Q MN1 neurons, CRABP1 level is reduced, revealing a correlation of motor neuron degeneration with Crabp1 down-regulation. Up-regulation of Crabp1 by Shh is mediated by glioma-associated oncogene homolog 1 (Gli1) that binds the Gli target sequence in Crabp1′s neuron-specific regulatory region upstream of minimal promoter. Gli1 binding triggers chromatin juxtaposition with minimal promoter, activating transcription. Motor neuron differentiation and Crabp1 up-regulation are both inhibited by blunting Shh with Gli inhibitor GANT61. Expression data mining of ALS and spinal muscular atrophy (SMA) motor neurons shows reduced CRABP1, coincided with reduction in Shh-Gli1 signaling components. This study reports motor neuron degeneration correlated with down-regulation in Crabp1 and Shh-Gli signaling. Shh-Gli up-regulation of Crabp1 involves specific chromatin remodeling. The physiological and pathological implication of this regulatory pathway in motor neuron degeneration is supported by gene expression data of ALS and SMA patients.

The role of RNA processing in the pathogenesis of motor neuron degeneration

2010 ◽  
Vol 12 ◽  
Author(s):  
Dirk Bäumer ◽  
Olaf Ansorge ◽  
Mara Almeida ◽  
Kevin Talbot
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Rna Processing ◽  
Muscular Atrophy ◽  
Rapid Expansion ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Temporal Gene Expression ◽  
Mrna Targeting

Motor neurons are large, highly polarised cells with very long axons and a requirement for precise spatial and temporal gene expression. Neurodegenerative disorders characterised by selective motor neuron vulnerability include various forms of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). A rapid expansion in knowledge on the pathophysiology of motor neuron degeneration has occurred in recent years, largely through the identification of genes leading to familial forms of ALS and SMA. The major emerging theme is that motor neuron degeneration can result from mutation in genes that encode factors important for ribonucleoprotein biogenesis and RNA processing, including splicing regulation, transcript stabilisation, translational repression and localisation of mRNA. Complete understanding of how these pathways interact and elucidation of specialised mechanisms for mRNA targeting and processing in motor neurons are likely to produce new targets for therapy in ALS and related disorders.

scholarly journals Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity

2016 ◽  
Vol 113 (41) ◽  
pp. E6209-E6218 ◽  
Author(s):  
Chunxing Yang ◽  
Eric W. Danielson ◽  
Tao Qiao ◽  
Jake Metterville ◽  
Robert H. Brown ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Actin Polymerization ◽  
Disease Model ◽  
Actin Binding ◽  
Wild Type ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Type Protein ◽  
Wild Type Protein

Mutations in the profilin 1 (PFN1) gene cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease caused by the loss of motor neurons leading to paralysis and eventually death. PFN1 is a small actin-binding protein that promotes formin-based actin polymerization and regulates numerous cellular functions, but how the mutations in PFN1 cause ALS is unclear. To investigate this problem, we have generated transgenic mice expressing either the ALS-associated mutant (C71G) or wild-type protein. Here, we report that mice expressing the mutant, but not the wild-type, protein had relentless progression of motor neuron loss with concomitant progressive muscle weakness ending in paralysis and death. Furthermore, mutant, but not wild-type, PFN1 forms insoluble aggregates, disrupts cytoskeletal structure, and elevates ubiquitin and p62/SQSTM levels in motor neurons. Unexpectedly, the acceleration of motor neuron degeneration precedes the accumulation of mutant PFN1 aggregates. These results suggest that although mutant PFN1 aggregation may contribute to neurodegeneration, it does not trigger its onset. Importantly, these experiments establish a progressive disease model that can contribute toward identifying the mechanisms of ALS pathogenesis and the development of therapeutic treatments.

scholarly journals Nutrient Effects on Motor Neurons and the Risk of Amyotrophic Lateral Sclerosis

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3804
Author(s):  
Polina S. Goncharova ◽  
Tatiana K. Davydova ◽  
Tatiana E. Popova ◽  
Maxim A. Novitsky ◽  
Marina M. Petrova ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Randomized Clinical Trials ◽  
Progression Rate ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Vitamin B9 ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable chronic progressive neurodegenerative disease with the progressive degeneration of motor neurons in the motor cortex and lower motor neurons in the spinal cord and the brain stem. The etiology and pathogenesis of ALS are being actively studied, but there is still no single concept. The study of ALS risk factors can help to understand the mechanism of this disease development and, possibly, slow down the rate of its progression in patients and also reduce the risk of its development in people with a predisposition toward familial ALS. The interest of researchers and clinicians in the protective role of nutrients in the development of ALS has been increasing in recent years. However, the role of some of them is not well-understood or disputed. The objective of this review is to analyze studies on the role of nutrients as environmental factors affecting the risk of developing ALS and the rate of motor neuron degeneration progression. Methods: We searched the PubMed, Springer, Clinical keys, Google Scholar, and E-Library databases for publications using keywords and their combinations. We analyzed all the available studies published in 2010–2020. Discussion: We analyzed 39 studies, including randomized clinical trials, clinical cases, and meta-analyses, involving ALS patients and studies on animal models of ALS. This review demonstrated that the following vitamins are the most significant protectors of ALS development: vitamin B12, vitamin E > vitamin C > vitamin B1, vitamin B9 > vitamin D > vitamin B2, vitamin B6 > vitamin A, and vitamin B7. In addition, this review indicates that the role of foods with a high content of cholesterol, polyunsaturated fatty acids, urates, and purines plays a big part in ALS development. Conclusion: The inclusion of vitamins and a ketogenic diet in disease-modifying ALS therapy can reduce the progression rate of motor neuron degeneration and slow the rate of disease progression, but the approach to nutrient selection must be personalized. The roles of vitamins C, D, and B7 as ALS protectors need further study.

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