scholarly journals Brief Review of the Role of Glycogen Synthase Kinase-3β in Amyotrophic Lateral Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Seong-Ho Koh ◽  
Wonki Baek ◽  
Seung H. Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Therapeutic Strategy ◽  
Glycogen Synthase ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Glycogen Synthase Kinase ◽  
Diverse Range ◽  
Symptom Progression ◽  
Lateral Sclerosis

Glycogen synthase kinase-3β(GSK-3β) is known to affect a diverse range of biological functions controlling gene expression, cellular architecture, and apoptosis. GSK-3βhas recently been identified as one of the important pathogenic mechanisms in motor neuronal death related to amyotrophic lateral sclerosis (ALS). Therefore, the development of methods to control GSK-3βcould be helpful in postponing the symptom progression of ALS. Here we discuss the known roles of GSK-3βin motor neuronal cell death in ALS and the possibility of employing GSK-3βmodulators as a new therapeutic strategy.

scholarly journals Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 10 (10) ◽  
pp. 675
Author(s):  
Hyun-Jun Choi ◽  
Sun Joo Cha ◽  
Jang-Won Lee ◽  
Hyung-Jun Kim ◽  
Kiyoung Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase 3 ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.

Evidence for a protective role of the CX3CL1/CX3CR1 axis in a model of amyotrophic lateral sclerosis

2019 ◽  
Vol 400 (5) ◽  
pp. 651-661 ◽  
Author(s):  
Chang Liu ◽  
Kun Hong ◽  
Huifang Chen ◽  
Yanping Niu ◽  
Weisong Duan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Communication System ◽  
Microglial Activation ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Degradation Pathway ◽  
Neuroprotective Effects ◽  
End Stage ◽  
Lateral Sclerosis

Abstract Aberrant microglial activation and neuroinflammation is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Fractalkine (CX3CL1) is mostly expressed on neuronal cells. The fractalkine receptor (CX3CR1) is predominantly expressed on microglia. Many progressive neuroinflammatory disorders show disruption of the CX3CL1/CX3CR1 communication system. But the exact role of the CX3CL1/CX3CR1 in ALS pathology remains unknown. F1 nontransgenic/CX3CR1+/− females were bred with SOD1G93A/CX3CR1+/− males to produce F2 SOD1G93A/CX3CR1−/−, SOD1G93A/CX3CR1+/+. We analyzed end-stage (ES) SOD1G93A/CX3CR1−/− mice and progression-matched SOD1G93A/CX3CR1+/+ mice. Our study showed that the male SOD1G93A/CX3CR1−/− mice died sooner than male SOD1G93A/CX3CR1+/+ mice. In SOD1G93A/CX3CR1−/− mice demonstrated more neuronal cell loss, more microglial activation and exacerbated SOD1 aggregation at the end-stage of ALS. The NF-κB pathway was activated; the autophagy-lysosome degradation pathway and the autophagosome maturation were impaired. Our results indicated that the absence of CX3CR1/CX3CL1 signaling in the central nervous system (CNS) may worsen neurodegeneration. The CX3CL1/CX3CR1 communication system has anti-inflammatory and neuroprotective effects and plays an important role in maintaining autophagy activity. This effort may lead to new therapeutic strategies for neuroprotection and provide a therapeutic target for ALS patients.

Celastrol Blocks Neuronal Cell Death and Extends Life in Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

2005 ◽  
Vol 2 (5) ◽  
pp. 246-254 ◽  
Author(s):  
Mahmoud Kiaei ◽  
Khatuna Kipiani ◽  
Susanne Petri ◽  
Junyu Chen ◽  
Noel Y. Calingasan ◽  
...  
Keyword(s):  
Cell Death ◽  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Transgenic Mouse Model ◽  
Lateral Sclerosis

scholarly journals Nonmuscle myosin IIB regulates Parkin-mediated mitophagy associated with amyotrophic lateral sclerosis-linked TDP-43

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Mi-Hee Jun ◽  
Jae-Woo Jang ◽  
Pureum Jeon ◽  
Soo-Kyung Lee ◽  
Sang-Hoon Lee ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Neuronal Cell ◽  
Mitochondrial Morphology ◽  
Nonmuscle Myosin ◽  
Potential Therapeutic Target ◽  
Selective Autophagy ◽  
Abnormal Mitochondria ◽  
Lateral Sclerosis

Abstract C-terminal fragments of Tar DNA-binding protein 43 (TDP-43) have been identified as the major pathological protein in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how they affect cellular toxicity and neurodegeneration, including the modulation process remains unknown. This study revealed that the C-terminal fragment of TDP-43 (TDP-25) was localized primarily to mitochondria and caused abnormal mitochondrial morphology, inducing Parkin-mediated mitophagy. Also, we discovered that the knockdown of selective autophagy receptors, such as TAX1BP, Optineurin, or NDP52 caused TDP-25 accumulation, indicating that TDP-25 was degraded by mitophagy. Interestingly, myosin IIB, a nonmuscle type of myosin and actin-based motor protein, is mostly colocalized to TDP-25 associated with abnormal mitochondria. In addition, myosin IIB inhibition by siRNA or blebbistatin induced mitochondrial accumulation of insoluble TDP-25 and Tom20, and reduced neuronal cell viability. Our results suggest a novel role of myosin IIB in mitochondrial degradation of toxic TDP-25. Therefore, we proposed that regulating myosin IIB activity might be a potential therapeutic target for neurodegenerative diseases associated with TDP-43 pathology.

scholarly journals Prion peptide induces neuronal cell death through a pathway involving glycogen synthase kinase 3

2003 ◽  
Vol 372 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Mar PÉREZ ◽  
Ana I. ROJO ◽  
Francisco WANDOSELL ◽  
Javier DÍAZ-NIDO ◽  
Jesús AVILA
Keyword(s):  
Cell Death ◽  
Glycogen Synthase ◽  
Neuronal Cell Death ◽  
Neuroblastoma Cells ◽  
Neuronal Cell ◽  
Dominant Negative ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Dominant Negative Mutant ◽  
Neuronal Cultures

Prion diseases are characterized by neuronal cell death, glial proliferation and deposition of prion peptide aggregates. An abnormal misfolded isoform of the prion protein (PrP) is considered to be responsible for this neurodegeneration. The PrP 106–126, a synthetic peptide obtained from the amyloidogenic region of the PrP, constitutes a model system to study prion-induced neurodegeneration as it retains the ability to trigger cell death in neuronal cultures. In the present study, we show that the addition of this prion peptide to cultured neurons increases the activity of glycogen synthase kinase 3 (GSK-3), which is accompanied by the enhanced phosphorylation of some microtubule-associated proteins including tau and microtubule-associated protein 2. Prion peptide-treated neurons become progressively atrophic, and die ultimately. Both lithium and insulin, which inhibit GSK-3 activity, significantly decrease prion peptide-induced cell death both in primary neuronal cultures and in neuroblastoma cells. Finally, the overexpression of a dominant-negative mutant of GSK-3 in transfected neuroblastoma cells efficiently prevents prion peptide-induced cell death. These results are consistent with the view that the activation of GSK-3 is a crucial mediator of prion peptide-induced neurodegeneration.

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