Role of the Akt/GSK-3β/CRMP-2 pathway in axon degeneration of dopaminergic neurons resulting from MPP+ toxicity

Wei, Fang; Gao, Guodong; Zhao, Haikang; Xia, Yi; Guo, Xiaodong; Li, Nan; Li, Yuqian; Yang, Yang; Chen, Lei; Wang, Qiang; Li, Lihong

doi:10.1016/j.brainres.2014.08.030

Cited by 39 publications

(35 citation statements)

References 41 publications

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“…Besides, the pathways of protein kinase B (AKT) and extracellular signal-regulated kinases ½ (ERK1/2), are involved in major processes accomplishing a wide variety of neural tasks, including glucose metabolism (Engelman et al 2006 ), cellular apoptosis and survival (Teng et al 2014 ), differentiation (Chan et al 2013 ), neural proliferation and migration (Dey et al 2005 ), neuro-protection (Zhang et al 2014 ), neuro-degeneration (Fang et al 2014 ), and synaptic signaling (Yoshii and Constantine-Paton 2014 . Moreover, AKT and ERK1/2 in brain tissue participate in the modulation of dopaminergic (Beaulieu et al 2006 ), muscarinic (Rosenblum et al 2000 ), adrenergic (Taraviras et al 2002 ), serotonergic (Cowen 2007 ), GABAergic (Balasubramanian et al 2004 ) and adenosinergic (Wiese et al 2007 ) neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats

Iturri

Joseph

Rodrigo

et al. 2015

Advances in Experimental Medicine and Biology

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The carotid body is the main mammalian oxygen-sensing organ regulating ventilation. Despite the carotid body is subjected of extensive anatomical and functional studies, little is yet known about the molecular pathways signaling the neurotransmission and neuromodulation of the chemoreflex activity. As kinases are molecules widely involved in motioning a broad number of neural processes, here we hypothesized that pathways of protein kinase B (AKT) and extracellular signal-regulated kinases ½ (ERK1/2) are implicated in the carotid body response to hypoxia. This hypothesis was tested using the in-vitro carotid body/carotid sinus nerve preparation ("en bloc") from Sprague Dawley adult rats. Preparations were incubated for 60 min in tyrode perfusion solution (control) or containing 1 μM of LY294002 (AKT inhibitor), or 1 μM of UO-126 (ERK1/2 inhibitor). The carotid sinus nerve chemoreceptor discharge rate was recorded under baseline (perfusion solution bubbled with 5 % CO(2) balanced in O(2)) and hypoxic (perfusion solution bubbled with 5 % CO(2) balanced in N(2)) conditions. Compared to control, both inhibitors significantly decreased the normoxic and hypoxic carotid body chemoreceptor activity. LY294002- reduced carotid sinus nerve discharge rate in hypoxia by about 20 %, while UO-126 reduces the hypoxic response by 45 %. We concluded that both AKT and ERK1/2 pathways are crucial for the carotid body intracellular signaling process in response to hypoxia.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats

Iturri

Joseph

Rodrigo

et al. 2015

Advances in Experimental Medicine and Biology

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“…(39) The Akt/GSK-3β/CRMP-2 pathway is involved in this model of axonal degeneration. Treatment with MPP + induces Ca 2+ release from mitochondria in isolated liver mitochondria of female Wistar rats.…”

Section: Does Ros Induce Neurodegenerative Disorders Through Neurite mentioning

confidence: 93%

“…(38) Microtubule-related axonal degeneration is divided into two types. (23,39) The first is anterograde degeneration, which involves degeneration proceeding from the cell soma to the distal end of a neurite. The second type is retrograde degeneration, which is also known as a “dying-back” process.…”

Section: Ros Treatment Induces Membrane Oxidation Microtubule Destabmentioning

confidence: 99%

“…(44) CRMP-2 is phosphorylated by glycogen synthesis-3 beta (GSK-3β) and cyclin dependent kinase 5. (39) Calpain is a protease that is activated in the presence of calcium ions and can cleave CRMP-2. (45) In our previous study, the ratio of CRMP-2 phosphorylation was remarkably increased in the cerebellum and hippocampus of young vitamin E-deficient and normal aged mice compared to age-matched controls.…”

Section: Ros Treatment Induces Membrane Oxidation Microtubule Destabmentioning

confidence: 99%

“…Several lines of evidence have demonstrated that axonal degeneration is observed in neurodegenerative disorders, such as AD, (23,51,55–57) Parkinson’s disease (PD), (34,35,39) Huntington’s disease (HD) and amyotrophic lateral sclerosis. (17,32,41,52,58–60) Neurite degeneration is induced in AD-transgenic mice, and reductions in the motor protein kinesin-1 accelerate amyloid deposition.…”

Section: Does Ros Induce Neurodegenerative Disorders Through Neurite mentioning

confidence: 99%

See 2 more Smart Citations

Reactive oxygen species induce neurite degeneration before induction of cell death

Fukui

2016

J. Clin. Biochem. Nutr.

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Reactive oxygen species (ROS) induce neuronal cell death in a time- and concentration-dependent manner. Treatment of cultured cells with a low concentration of hydrogen peroxide induces neurite degeneration, but not cell death. Neurites (axons and dendrites) are vulnerable to ROS. Neurite degeneration (shrinkage, accumulation, and fragmentation) has been found in neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, the mechanism of ROS-related neurite degeneration is not fully understood. Many studies have demonstrated the relationship between mitochondrial dysfunction and microtubule destabilization. These dysfunctions are deeply related to changes in calcium homeostasis and ROS production in neurites. Treatment with antioxidant substances, such as vitamin E, prevents neurite degeneration in cultured cells. This review describes the possibility that ROS induces neurite degeneration before the induction of cell death.

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Induction of CRMP‐2 phosphorylation by CDK5 restricts the repair of damaged optic nerve

Chen

Yuan

Gao

et al. 2018

Journal Cellular Physiology

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Objective To study the mechanism of collapsin response mediator protein‐2 (CRMP‐2) phosphorylation changes and cyclin‐dependent kinase 5 (CDK5) expression after optic nerve injury. Methods Optic nerve injury rat models were constructed, the messenger RNA (mRNA) level of CRMP‐2 in optic nerve tissues was determined by quantitative reverse transcription polymerase chain reaction (qRT‐PCR) after building models 0, 3, 7, and 14 days. The protein expression of CRMP‐2, phospho‐CRMP‐2 (p‐CRMP‐2), and CDK5 were also determined by western blot analysis. Lentivirus overexpressing CRMP‐2 and CRMP‐2 small interfering RNA (siRNA) plasmid were designed and transfected to retina ganglion cells (RGCs), and then the neurites outgrowth of RGCs were cultured with CDK5 inhibitor or CDK5 activator was determined by tubulin staining. Inhibition on CDK5 promotes injured optic nerve by using carrying CDK5 siRNA inject into vitreous chamber. Results There was no significant change in CRMP‐2 expression in optic nerve injury rat, while p‐CRMP‐2 expression was evidently increased compared with sham operation group. The expression level of CDK5 in optic nerve tissue was upregulated after optic nerve injury in rat, and the upward trend of p‐CRMP‐2 and CDK5 was consistent with the time after the injury was prolonged. Inhibition on CDK5 evidently decreased the expression of p‐CRMP‐2. CDK5 siRNA had an obvious repair effect on the injured optic nerve. Conclusion The increase of CDK5 activity can lead to CRMP‐2 hyperphosphorylation, which results in the difficult repair of damaged optic nerve. Therefore, inhibition on CDK5 could promote the repair of damaged optic nerve.

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Role of the Akt/GSK-3β/CRMP-2 pathway in axon degeneration of dopaminergic neurons resulting from MPP+ toxicity

Cited by 39 publications

References 41 publications

Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats

Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats

Reactive oxygen species induce neurite degeneration before induction of cell death

Induction of CRMP‐2 phosphorylation by CDK5 restricts the repair of damaged optic nerve

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