scholarly journals GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration

2017 ◽  
Vol 216 (2) ◽  
pp. 477-493 ◽  
Author(s):  
Shuji Wakatsuki ◽  
Shinji Tokunaga ◽  
Megumi Shibata ◽  
Toshiyuki Araki
Keyword(s):  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Physiological Function ◽  
Glycogen Synthase ◽  
Bcl2 Family ◽  
Adenosine Triphosphate Production ◽  
Bcl2 Family Member ◽  
Catabolic Process ◽  
Degenerating Axons

Macroautophagy is a catabolic process, in which portions of cytoplasm or organelles are delivered to lysosomes for degradation. Emerging evidence has indicated a pathological connection between axonal degeneration and autophagy. However, the physiological function and induction mechanism of autophagy in axons remain elusive. We herein show that, through activation of BECLIN1, glycogen synthase kinase 3B (GSK3B)–mediated phosphorylation of BCL2 family member MCL1 induces axonal autophagy and axonal degeneration. Phosphorylated MCL1 is ubiquitinated by the FBXW7 ubiquitin ligase and degraded by the proteasome, thereby releasing BECLIN1 to induce axonal autophagy. Axonal autophagy contributes to local adenosine triphosphate production in degenerating axons and the exposure of phosphatidylserine—an “eat-me” signal for phagocytes—on transected axons and is required for normal recruitment of phagocytes to axonal debris in vivo. These results suggest that GSK3B–MCL1 signaling to regulate autophagy might be important for the successful completion of Wallerian degeneration.

scholarly journals Ubiquitin Expression in Degenerating Axons of Equine Cervical Compressive Myelopathy

1996 ◽  
Vol 33 (3) ◽  
pp. 356-359 ◽  
Author(s):  
B. S. Jortner ◽  
W. K. Scarratt ◽  
P. D. Modransky ◽  
A. Walton ◽  
S. K. Perkins
Keyword(s):  
Wallerian Degeneration ◽  
Stress Protein ◽  
Nerve Fibers ◽  
Axonal Swelling ◽  
Myelinated Nerve ◽  
Cervical Compressive Myelopathy ◽  
Compressive Myelopathy ◽  
Young Horses ◽  
Catabolic Process ◽  
Degenerating Axons

Neuropathologic examination revealed axonal swelling and breakdown leading to Wallerian degeneration of affected myelinated nerve fibers in the spinal cord white matter of four young horses with equine cervical compressive myelopathy. Immunohistochemical reactions for the cell stress protein ubiquitin revealed an enhanced presence in the swollen axons, which may reflect a role for ubiquitin in the neuronal catabolic process of axonal compression and degeneration in this myelopathy.

scholarly journals A Liquid-to-Solid Phase Transition Enhances the Catalytic Activity of SARM1

2020 ◽  
Author(s):  
Heather S. Loring ◽  
Paul R. Thompson
Keyword(s):  
Phase Transition ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Solid Phase ◽  
Neurological Diseases ◽  
Promising Therapeutic Target ◽  
Solid Phase Transition

ABSTRACTSterile alpha and toll/interleukin receptor (TIR) motif–containing protein 1 (SARM1) is a neuronally expressed NAD+ glycohydrolase whose activity is increased in response to various stressors. The consequent depletion of NAD+ triggers axonal degeneration (i.e., Wallerian degeneration), which is a characteristic feature of neurological diseases, including peripheral neuropathies and traumatic brain injury. Notably, SARM1 knockout mice show minimal degeneration in models of peripheral neuropathy and traumatic brain injury, making SARM1 a promising therapeutic target. However, the development of SARM1 inhibitors has been challenging as the purified enzyme is largely inactive. Herein, we report that SARM1 activity is increased ∼2000–fold by a liquid-to-solid phase transition. These findings provide critical insights into SARM1 biochemistry with important implications for the situation in vivo. Moreover, they will facilitate the discovery of novel SARM1–targeted therapeutics.Graphical Abstract

scholarly journals Rapid depletion of ESCRT protein Vps4 underlies injury-induced autophagic impediment and Wallerian degeneration

2019 ◽  
Vol 5 (2) ◽  
pp. eaav4971 ◽  
Author(s):  
Haiqiong Wang ◽  
Xuejie Wang ◽  
Kai Zhang ◽  
Qingyao Wang ◽  
Xu Cao ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Essential Gene ◽  
Underlying Mechanism ◽  
Autophagic Flux ◽  
In Vivo Models ◽  
Axon Injury

Injured axons undergo a controlled, self-destruction process, known as Wallerian degeneration. However, the underlying mechanism remains elusive. Using the Drosophila wing nerve as a model, we identify the ESCRT component Vps4 as a previously unidentified essential gene for axonal integrity. Up-regulation of Vps4 remarkably delays degeneration of injured axons. We further reveal that Vps4 is required and sufficient to promote autophagic flux in axons and mammalian cells. Moreover, using both in vitro and in vivo models, we show that the function of Vps4 in maintaining axonal autophagy and suppressing Wallerian degeneration is conserved in mammals. Last, we uncover that Vps4 protein is rapidly depleted in injured mouse axons, which may underlie the injury-induced autophagic impediment and the subsequent axonal degeneration. Together, Vps4 and ESCRT may represent a novel signal transduction mechanism in axon injury and Wallerian degeneration.

scholarly journals A neuroprotective agent that inactivates prodegenerative TrkA and preserves mitochondria

2017 ◽  
Vol 216 (11) ◽  
pp. 3655-3675 ◽  
Author(s):  
Konstantin Feinberg ◽  
Adelaida Kolaj ◽  
Chen Wu ◽  
Natalie Grinshtein ◽  
Jonathan R. Krieger ◽  
...  
Keyword(s):  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Kinase Inhibitor ◽  
Sympathetic Neurons ◽  
Energy Deficit ◽  
Axon Degeneration ◽  
Therapeutic Drug ◽  
Early Event ◽  
Sod1 Mutant

Axon degeneration is an early event and pathological in neurodegenerative conditions and nerve injuries. To discover agents that suppress neuronal death and axonal degeneration, we performed drug screens on primary rodent neurons and identified the pan-kinase inhibitor foretinib, which potently rescued sympathetic, sensory, and motor wt and SOD1 mutant neurons from trophic factor withdrawal-induced degeneration. By using primary sympathetic neurons grown in mass cultures and Campenot chambers, we show that foretinib protected neurons by suppressing both known degenerative pathways and a new pathway involving unliganded TrkA and transcriptional regulation of the proapoptotic BH3 family members BimEL, Harakiri,and Puma, culminating in preservation of mitochondria in the degenerative setting. Foretinib delayed chemotherapy-induced and Wallerian axonal degeneration in culture by preventing axotomy-induced local energy deficit and preserving mitochondria, and peripheral Wallerian degeneration in vivo. These findings identify a new axon degeneration pathway and a potentially clinically useful therapeutic drug.

scholarly journals MEK inhibition causes Bim stabilization and sensitivity to Bcl2 family member inhibitors in RAS-MAPK mutated neuroblastoma

2020 ◽  
Author(s):  
Thomas F Eleveld ◽  
Lindy Vernooij ◽  
Linda Schild ◽  
Bianca Koopmans ◽  
Lindy K Alles ◽  
...  
Keyword(s):  
Family Member ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Neuroblastoma Cells ◽  
Mek Inhibition ◽  
Bcl2 Family ◽  
Increased Sensitivity ◽  
Bcl2 Family Member

AbstractMutations affecting the RAS-MAPK pathway occur frequently in relapsed neuroblastoma tumors and are associated with response to MEK inhibition in vitro. However, these inhibitors alone do not lead to tumor regression in vivo, indicating the need for combination therapy. Through high throughput combination screening we identify Trametinib and inhibitors of the BCL2 family (Navitoclax and Venetoclax) as a promising combination in neuroblastoma cells with RAS-MAPK mutations. In these lines, inhibiting the RAS-MAPK pathway leads to Bim stabilization and increased sensitivity to compounds inhibiting Bim binding to Bcl2 family members. Combining Trametinib with BCL2 inhibitors causes increased growth inhibition compared to Trametinib only in NRAS mutant SKNAS xenografts, while BCL2 inihibitors alone do not affect growth of these tumors. These results show that MEK inhibitors and specific Bcl2 family member inhibitors are a potent combination for RAS-MAPK mutated neuroblastoma tumors.

Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

2020 ◽  
Vol 20 (12) ◽  
pp. 1059-1073 ◽  
Author(s):  
Ahmad Abu Turab Naqvi ◽  
Gulam Mustafa Hasan ◽  
Md. Imtaiyaz Hassan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Glycogen Synthase ◽  
Paired Helical Filaments ◽  
Tau Hyperphosphorylation ◽  
Microtubule Stabilization ◽  
Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

scholarly journals GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 610
Author(s):  
Robin Park ◽  
Andrew L. Coveler ◽  
Ludimila Cavalcante ◽  
Anwaar Saeed
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
In Vivo Models ◽  
Gsk 3Β ◽  
Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

scholarly journals Functional Characterization of the mazEF Toxin-Antitoxin System in the Pathogenic Bacterium Agrobacterium tumefaciens

2021 ◽  
Vol 9 (5) ◽  
pp. 1107
Author(s):  
Wonho Choi ◽  
Yoshihiro Yamaguchi ◽  
Ji-Young Park ◽  
Sang-Hyun Park ◽  
Hyeok-Won Lee ◽  
...  
Keyword(s):  
Agrobacterium Tumefaciens ◽  
Physiological Function ◽  
Functional Characterization ◽  
Site Directed Mutagenesis ◽  
In Vitro Assays ◽  
Cell Growth Inhibition ◽  
The Right

Agrobacterium tumefaciens is a pathogen of various plants which transfers its own DNA (T-DNA) to the host plants. It is used for producing genetically modified plants with this ability. To control T-DNA transfer to the right place, toxin-antitoxin (TA) systems of A. tumefaciens were used to control the target site of transfer without any unintentional targeting. Here, we describe a toxin-antitoxin system, Atu0939 (mazE-at) and Atu0940 (mazF-at), in the chromosome of Agrobacterium tumefaciens. The toxin in the TA system has 33.3% identity and 45.5% similarity with MazF in Escherichia coli. The expression of MazF-at caused cell growth inhibition, while cells with MazF-at co-expressed with MazE-at grew normally. In vivo and in vitro assays revealed that MazF-at inhibited protein synthesis by decreasing the cellular mRNA stability. Moreover, the catalytic residue of MazF-at was determined to be the 24th glutamic acid using site-directed mutagenesis. From the results, we concluded that MazF-at is a type II toxin-antitoxin system and a ribosome-independent endoribonuclease. Here, we characterized a TA system in A. tumefaciens whose understanding might help to find its physiological function and to develop further applications.

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