CXCR2 increases in ALS cortical neurons and its inhibition prevents motor neuron degeneration in vitro and improves neuromuscular function in SOD1G93A mice

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.

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Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo

Neuroscience ◽

10.1016/j.neuroscience.2006.09.064 ◽

2007 ◽

Vol 144 (3) ◽

pp. 991-1003 ◽

Cited By ~ 92

Author(s):

L. Chi ◽

Y. Ke ◽

C. Luo ◽

D. Gozal ◽

R. Liu

Keyword(s):

Motor Neuron ◽

Reduced Glutathione ◽

Motor Neuron Degeneration ◽

Neuron Degeneration

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Alterations in AQP4 expression and polarization in the course of motor neuron degeneration in SOD1G93A mice

Molecular Medicine Reports ◽

10.3892/mmr.2017.6786 ◽

2017 ◽

Vol 16 (2) ◽

pp. 1739-1746 ◽

Cited By ~ 7

Author(s):

Jiaying Dai ◽

Weihao Lin ◽

Minying Zheng ◽

Qiang Liu ◽

Baixuan He ◽

...

Keyword(s):

Motor Neuron ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Aqp4 Expression ◽

Sod1g93a Mice

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A microfluidic approach to rescue ALS motor neuron degeneration using rapamycin

Scientific Reports ◽

10.1038/s41598-021-97405-1 ◽

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.

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