The contribution of ciliary neurotrophic factor receptors to adult motor neuron survival in vivo is specific to insult type and distinct from that for embryonic motor neurons

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

Veterinary Pathology ◽

10.1354/vp.08-vp-0239-b-bc ◽

2008 ◽

Vol 46 (3) ◽

pp. 514-519 ◽

Cited By ~ 18

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.

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Adult ciliary neurotrophic factor receptors help maintain facial motor neuron choline acetyltransferase expression in vivo following nerve crush

The Journal of Comparative Neurology ◽

10.1002/cne.24126 ◽

2016 ◽

Vol 525 (5) ◽

pp. 1206-1215 ◽

Cited By ~ 1

Author(s):

Nancy Lee ◽

Carolyn E. Rydyznski ◽

Matthew S. Rasch ◽

Dennis S. Trinh ◽

A. John MacLennan

Keyword(s):

Motor Neuron ◽

Choline Acetyltransferase ◽

Neurotrophic Factor ◽

Ciliary Neurotrophic Factor ◽

Nerve Crush ◽

Facial Motor Neuron

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

eLife ◽

10.7554/elife.06500 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 5

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.

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