Defective neurite outgrowth in aphidicolin/cAMP‐induced motor neurons expressing mutant Cu/Zn superoxide dismutase

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. Although many drugs have entered clinical trials, few have shown effectiveness in the treatment of ALS. Other studies have shown that the stimulation of α7 nicotinic acetylcholine receptor (nAChR) can have neuroprotective effects in some models of neurodegenerative disease, as well as prevent glutamate-induced motor neuronal death. However, the effect of α7 nAChR agonists on ALS-associated mutant copper–zinc superoxide dismutase 1 (SOD1) aggregates in motor neurons remains unclear. In the present study, we examined whether α7 nAChR activation had a neuroprotective effect against SOD1G85R-induced toxicity in a cellular model for ALS. We found that α7 nAChR activation by PNU282987, a selective agonist of α7 nAChR, exhibited significant neuroprotective effects against SOD1G85R-induced toxicity via the reduction of intracellular protein aggregates. This reduction also correlated with the activation of autophagy through the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) signaling pathway. Furthermore, the activation of α7 nAChRs was found to increase the biogenesis of lysosomes by inducing translocation of the transcription factor EB (TFEB) into the nucleus. These results support the therapeutic potential of α7 nAChR activation in diseases that are characterized by SOD1G85R aggregates, such as ALS.

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Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

Neurology Research International ◽

10.1155/2012/323261 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Yoshiaki Furukawa

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

Motor Neurons ◽

Wild Type ◽

Sporadic Als ◽

Familial Form ◽

Recent Developments ◽

Lateral Sclerosis

Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, manyin vitroandin vivostudies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations insod1gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

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Hindlimb Motor Neurons Require Cu/Zn Superoxide Dismutase for Maintenance of Neuromuscular Junctions

American Journal Of Pathology ◽

10.1016/s0002-9440(10)65162-0 ◽

1999 ◽

Vol 155 (2) ◽

pp. 663-672 ◽

Cited By ~ 74

Author(s):

Dorothy G. Flood ◽

Andrew G. Reaume ◽

John A. Gruner ◽

Eric K. Hoffman ◽

James D. Hirsch ◽

...

Keyword(s):

Superoxide Dismutase ◽

Motor Neurons ◽

Neuromuscular Junctions

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Voltage-Dependent Sodium Channels in Spinal Cord Motor Neurons Display Rapid Recovery From Fast Inactivation in a Mouse Model of Amyotrophic Lateral Sclerosis

Journal of Neurophysiology ◽

10.1152/jn.00566.2006 ◽

2006 ◽

Vol 96 (6) ◽

pp. 3314-3322 ◽

Cited By ~ 37

Author(s):

Cristina Zona ◽

Massimo Pieri ◽

Irene Carunchio

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

Mouse Model ◽

Sodium Channels ◽

Motor Neurons ◽

Fast Inactivation ◽

Patch Clamp Recording ◽

Voltage Dependent ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a substantial loss of motor neurons in the spinal cord, brain stem, and motor cortex. Previous evidence showed that in a mouse model of a familial form of ALS expressing high levels of the human mutated protein Cu,Zn superoxide dismutase (Gly93→Ala, G93A), the firing properties of single motor neurons are altered to induce neuronal hyperexcitability. To determine whether the functionality of the macroscopic voltage-dependent Na+ currents is modified in G93A motor neurons, in the present work their physiological properties were examined. The voltage-dependent sodium channels were studied in dissociated motor neurons in culture from nontransgenic mice (Control), from transgenic mice expressing high levels of the human wild-type protein [superoxide dismutase 1 (SOD1)], and from G93A mice, using the whole cell configuration of the patch-clamp recording technique. The voltage dependency of activation and of steady-state inactivation, the kinetics of fast inactivation and slow inactivation of the voltage-dependent Na+ channels were not modified in the mutated mice. Conversely, the recovery from fast inactivation was significantly faster in G93A motor neurons than that in Control and SOD1. The recovery from fast inactivation was still significantly faster in G93A motor neurons exposed for different times (3–48 h) and concentrations (5–500 μM) to edaravone, a free-radical scavenger. Clarification of the importance of these changes in membrane ion channel functionality may have diagnostic and therapeutic implications in the pathogenesis of ALS.

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Effect of inhibition of superoxide dismutase on motor neurons during growth: Comparison of phosphorylated and non-phosphorylated neurofilament-containing spinal neurons by histogram distribution

Brain Research ◽

10.1016/j.brainres.2012.06.014 ◽

2012 ◽

Vol 1470 ◽

pp. 11-16 ◽

Cited By ~ 2

Author(s):

Risa Isonaka ◽

Takashi Katakura ◽

Tadashi Kawakami

Keyword(s):

Superoxide Dismutase ◽

Motor Neurons ◽

Spinal Neurons

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Human superoxide dismutase 1 overexpression in motor neurons of Caenorhabditis elegans causes axon guidance defect and neurodegeneration

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2013.09.003 ◽

2014 ◽

Vol 35 (4) ◽

pp. 837-846 ◽

Cited By ~ 12

Author(s):

Jia Li ◽

Ting Li ◽

Xiaojie Zhang ◽

Yu Tang ◽

Juan Yang ◽

...

Keyword(s):

Superoxide Dismutase ◽

Caenorhabditis Elegans ◽

Axon Guidance ◽

Motor Neurons ◽

Superoxide Dismutase 1

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A Role for Copper in the Toxicity of Zinc-Deficient Superoxide Dismutase to Motor Neurons in Amyotrophic Lateral Sclerosis

Antioxidants and Redox Signaling ◽

10.1089/ars.2009.2574 ◽

2009 ◽

Vol 11 (7) ◽

pp. 1627-1639 ◽

Cited By ~ 48

Author(s):

Kari A. Trumbull ◽

Joseph S. Beckman

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

Motor Neurons ◽

Lateral Sclerosis

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α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate receptors in spinal cord motor neurons are altered in transgenic mice overexpressing human cu,zn superoxide dismutase (Gly93→Ala) mutation

Neuroscience ◽

10.1016/s0306-4522(03)00588-8 ◽

2003 ◽

Author(s):

M Pieri

Keyword(s):

Spinal Cord ◽

Superoxide Dismutase ◽

Transgenic Mice ◽

Motor Neurons

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Increased Expression of a Proline-Rich Akt Substrate (PRAS40) in Human Copper/Zinc-Superoxide Dismutase Transgenic Rats Protects Motor Neurons from Death after Spinal Cord Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600501 ◽

2007 ◽

Vol 28 (1) ◽

pp. 44-52 ◽

Cited By ~ 18

Author(s):

Fengshan Yu ◽

Purnima Narasimhan ◽

Atsushi Saito ◽

Jing Liu ◽

Pak H Chan

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Superoxide Dismutase ◽

Motor Neurons ◽

Focal Cerebral Ischemia ◽

Akt Inhibitor ◽

Copper Zinc Superoxide Dismutase ◽

Zinc Superoxide Dismutase ◽

Cord Injury ◽

Copper Zinc

The serine-threonine kinase, Akt, plays an important role in the cell survival signaling pathway. A proline-rich Akt substrate, PRAS40, has been characterized, and an increase in phospho-PRAS40 (pPRAS40) is neuroprotective after transient focal cerebral ischemia. However, the involvement of PRAS40 in the cell death/survival pathway after spinal cord injury (SCI) is unclear. Liposome-mediated PRAS40 transfection was performed to study whether overexpression of pPRAS40 is neuroprotective. We further examined the expression of pPRAS40 after SCI by immunohistochemistry and Western blot using copper/zinc-superoxide dismutase (SOD1) transgenic (Tg) rats and wild-type (Wt) littermates. We then examined the relationship between PRAS40 and Akt by injection of LY294002, a phosphatidylinositol 3-kinase (PI3K) pathway inhibitor, or Akt inhibitor IV, a compound that inhibits Akt activation after SCI. Our data demonstrated that increased pPRAS40 resulted in survival of more motor neurons compared with control complementary DNA transfection. Phosphorylated PRAS40 increased in the Wt rats after SCI, whereas there was a greater and prolonged increase in the SOD1 Tg rats. Coimmunoprecipitation showed that binding of pPRAS40 with 14-3-3 increased 1 day after SCI in the Wt rats, whereas there was a significant increase in the Tg rats. The inhibitor studies showed that phospho-Akt and pPRAS40 were decreased after injection of LY294002 or Akt inhibitor IV. We conclude that an increase in pPRAS40 by transfection after SCI results in survival of motor neurons, and overexpression of SOD1 in the Tg rats results in an increase in endogenous pPRAS40 and a decrease in motor neuron death through the PI3K/Akt pathway.

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