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https://www.readbyqxmd.com/read/28505105/new-functions-of-apc-c-ubiquitin-ligase-in-the-nervous-system-and-its-role-in-alzheimer-s-disease
#1
REVIEW
Tanja Fuchsberger, Ana Lloret, Jose Viña
The E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C) regulates important processes in cells, such as the cell cycle, by targeting a set of substrates for degradation. In the last decade, APC/C has been related to several major functions in the nervous system, including axon guidance, synaptic plasticity, neurogenesis, and neuronal survival. Interestingly, some of the identified APC/C substrates have been related to neurodegenerative diseases. There is an accumulation of some degradation targets of APC/C in Alzheimer's disease (AD) brains, which suggests a dysregulation of the protein complex in the disorder...
May 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28408624/activated-protein-c-inhibits-neutrophil-extracellular-trap-formation-in-vitro-and-activation-in-vivo
#2
Laura D Healy, Cristina Puy, José A Fernández, Annachiara Mitrugno, Ravi S Keshari, Nyiawung A Taku, Tiffany T Chu, Xiao Xu, András Gruber, Florea Lupu, John H Griffin, Owen J T McCarty
Activated protein C (APC) is a multi-functional serine protease with anticoagulant, cytoprotective, and anti-inflammatory activities. In addition to the cytoprotective effects of APC on endothelial cells, podocytes, and neurons, APC cleaves and detoxifies extracellular histones, a major component of neutrophil extracellular traps (NETs). NETs promote pathogen clearance but also can lead to thrombosis; the pathways that negatively regulate NETosis are largely unknown. Thus, we studied whether APC is capable of directly inhibiting NETosis via receptor-mediated cell signaling mechanisms...
April 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28396402/apc-c-cdh1-rock2-pathway-controls-dendritic-integrity-and-memory
#3
Verónica Bobo-Jiménez, María Delgado-Esteban, Julie Angibaud, Irene Sánchez-Morán, Antonio de la Fuente, Javier Yajeya, U Valentin Nägerl, José Castillo, Juan P Bolaños, Angeles Almeida
Disruption of neuronal morphology contributes to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD). However, the underlying molecular mechanisms are unknown. Here, we show that postnatal deletion of Cdh1, a cofactor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase in neurons [Cdh1 conditional knockout (cKO)], disrupts dendrite arborization and causes dendritic spine and synapse loss in the cortex and hippocampus, concomitant with memory impairment and neurodegeneration, in adult mice...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28245468/raf-kinase-inhibitor-protein-attenuates-ischemic-induced-microglia-cell-apoptosis-and-activation-through-nf-%C3%AE%C2%BAb-pathway
#4
Li Su, Rongrong Zhang, Yuanyuan Chen, Zhenyu Zhu, Chao Ma
BACKGROUND: Acute ischemic stroke is one of the most important factors leading to disability and death with the characterization of accumulated neuron death and injured supportive neurovascular structures. Raf-1 kinase inhibitory protein (RKIP) is a key molecule in cell response to survival or death stimuli. However, the role of RKIP in stroke is worthy to be further studied. METHODS: We used lentivirus mediated RKIP knockdown and overexpression to investigate the effect of RKIP on animal models of focal cerebral ischemia...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28241697/-alterations-of-mirna-profiles-and-function-analysis-in-paraquat-induced-apoptosis-of-hnpcs
#5
M Huang, Q Cai, H H Li, D Lou
Objective: To investigate the impacts of paraquat on microRNA profiles in apoptosis of human neural progenitor cells (hNPCs) and to explore miRNA targets and biological functions. Methods: We used hNPCs as a popular in vitro cell model system for characterizing the neurotoxicity. Cell apoptosis was detected by Annexin V-APC/7-AAD after 24 h treatment with different concentrations of PQ (0, 5, 10, 20, 40, 80 μmol/L). Microarray profiling expression of PQ treated cell line and their corresponding control was determined and differentially expression miRNAs were confirmed by quantitatively real-time PCR...
January 20, 2017: Chinese Journal of Industrial Hygiene and Occupational Diseases
https://www.readbyqxmd.com/read/28161197/icariin-enhances-remyelination-process-after-acute-demyelination-induced-by-cuprizone-exposure
#6
Yifan Zhang, Linlin Yin, Na Zheng, Li Zhang, Jianghong Liu, Weixiong Liang, Qi Wang
Pathology are still progressive and cumulative in the remission course of relapsing-remitting MS (RRMS), thus drug treatment during the remission period may play a great role for the regeneration of the myelin sheath. C57BL/6 mice were fed with cuprizone (CPZ, 0.2% w/w) for 5 weeks to induce acute demyelination and oligodendrocytes degeneration, after which CPZ was withdrawn to allow recovery. Icariin (ICA, 6.25, 12.5 and 25mg/kg/day), vehicle (0.5% sodium carboxymethyl cellulose solution) or water was administrated orally to mice for 1 week after CPZ withdrawal...
February 1, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28103118/park2-dependent-mitophagy-induced-by-acidic-postconditioning-protects-against-focal-cerebral-ischemia-and-extends-the-reperfusion-window
#7
Zhe Shen, Yanrong Zheng, Jiaying Wu, Ying Chen, Xiaoli Wu, Yiting Zhou, Yang Yuan, Shousheng Lu, Lei Jiang, Zhenghong Qin, Zhong Chen, Weiwei Hu, Xiangnan Zhang
Prompt reperfusion after cerebral ischemia is critical for neuronal survival. Any strategies that extend the limited reperfusion window will be of great importance. Acidic postconditioning (APC) is a mild acidosis treatment that involves inhaling CO2 during reperfusion following ischemia. APC attenuates ischemic brain injury although the underlying mechanisms have not been elucidated. Here we report that APC reinforces ischemia-reperfusion-induced mitophagy in middle cortical artery occlusion (MCAO)-treated mice, and in oxygen-glucose deprivation (OGD)-treated brain slices and neurons...
March 4, 2017: Autophagy
https://www.readbyqxmd.com/read/28056224/recombinant-fowlpox-virus-vector-based-vaccines-expression-kinetics-dissemination-and-safety-profile-following-intranasal-delivery
#8
David G Townsend, Shubhanshi Trivedi, Ronald J Jackson, Charani Ranasinghe
We have previously established that mucosal uptake of recombinant fowlpox virus (rFPV) vaccines is far superior to other vector-based vaccines. Specifically, intranasal priming with rFPV vaccines can recruit unique antigen-presenting cells, which induce excellent mucosal and systemic HIV-specific CD8+ T-cell immunity. In this study, we have for the first time investigated the in vivo dissemination, safety and expression kinetics of rFPV post intranasal delivery using recombinant viruses expressing green fluorescent protein or mCherry...
March 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28041906/apc-c-fzr-cdh1-dependent-regulation-of-planar-cell-polarity-establishment-via-nek2-kinase-acting-on-dishevelled
#9
Ursula Weber, Marek Mlodzik
The Anaphase-Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase, well known for its role in cell-cycle progression. However, it has been linked to additional functions, mainly in neuronal contexts, when using the co-activator Cdh1/Fzr. Here, our data indicate a post-mitotic requirement for the APC/C(Fzr/Cdh1) in epithelial cell patterning and planar cell polarity (PCP) in Drosophila. PCP signaling is critical for development by establishing cellular asymmetries and orientation within the plane of an epithelium, via differential localization of distinct complexes of core PCP factors...
January 9, 2017: Developmental Cell
https://www.readbyqxmd.com/read/27939356/the-origins-of-rimmed-vacuoles-and-granulovacuolar-degeneration-bodies-are-associated-with-the-wnt-signaling-pathway
#10
Yukari Murata-Shinozaki, Tetsuya Takahashi, Tomoyasu Matsubara, Hirofumi Maruyama, Yuishin Izumi, Masayasu Matsumoto
Inclusion-body myositis (IBM) and Alzheimer's disease (AD) are biochemically characterized by the presence of aggregated β-amyloid protein and tau protein. In addition, both diseases are pathologically characterized by vacuolar changes, including rimmed vacuoles (RVs) in IBM and granulovacuolar degeneration (GVD) in AD. Previously, we demonstrated that RVs and GVD bodies are associated with a set of common molecules, leading us to speculate that both RVs and GVD bodies originate from similar structures on the plasma membrane of muscle cells and neuronal cells, namely, the neuromuscular junction (NMJ) and the postsynaptic spine especially in terms of Wnt signaling pathway...
December 7, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27889750/metformin-protects-neurons-against-oxygen-glucose-deprivation-reoxygenation-induced-injury-by-down-regulating-mad2b
#11
Xianfang Meng, Guangpin Chu, Zhihua Yang, Ping Qiu, Yue Hu, Xiaohe Chen, Wenpeng Peng, Chen Ye, Fang-Fang He, Chun Zhang
BACKGROUND/AIMS: Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27852007/apc-conditional-knock-out-mouse-is-a-model-of-infantile-spasms-with-elevated-neuronal-%C3%AE-catenin-levels-neonatal-spasms-and-chronic-seizures
#12
Antonella Pirone, Jonathan Alexander, Lauren A Lau, David Hampton, Andrew Zayachkivsky, Amy Yee, Audrey Yee, Michele H Jacob, Chris G Dulla
Infantile spasms (IS) are a catastrophic childhood epilepsy syndrome characterized by flexion-extension spasms during infancy that progress to chronic seizures and cognitive deficits in later life. The molecular causes of IS are poorly defined. Genetic screens of individuals with IS have identified multiple risk genes, several of which are predicted to alter β-catenin pathways. However, evidence linking malfunction of β-catenin pathways and IS is lacking. Here, we show that conditional deletion in mice of the adenomatous polyposis coli gene (APC cKO), the major negative regulator of β-catenin, leads to excessive β-catenin levels and multiple salient features of human IS...
February 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/27849007/two-ptp-receptors-mediate-cspg-inhibition-by-convergent-and-divergent-signaling-pathways-in-neurons
#13
Yosuke Ohtake, Daniella Wong, P M Abdul-Muneer, Michael E Selzer, Shuxin Li
Receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member LAR act as transmembrane receptors that mediate growth inhibition of chondroitin sulfate proteoglycans (CSPGs). Inhibition of either receptor increases axon growth into and beyond scar tissues after CNS injury. However, it is unclear why neurons express two similar CSPG receptors, nor whether they use the same or different intracellular pathways. We have now studied the signaling pathways of these two receptors using N2A cells and primary neurons derived from knockout mice...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27802274/topology-cross-frequency-and-same-frequency-band-interactions-shape-the-generation-of-phase-amplitude-coupling-in-a-neural-mass-model-of-a-cortical-column
#14
Roberto C Sotero
Phase-amplitude coupling (PAC), a type of cross-frequency coupling (CFC) where the phase of a low-frequency rhythm modulates the amplitude of a higher frequency, is becoming an important indicator of information transmission in the brain. However, the neurobiological mechanisms underlying its generation remain undetermined. A realistic, yet tractable computational model of the phenomenon is thus needed. Here we analyze a neural mass model of a cortical column, comprising fourteen neuronal populations distributed across four layers (L2/3, L4, L5 and L6)...
November 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27758767/2016-scientific-sessions-sol-sherry-distinguished-lecturer-in-thrombosis-thrombotic-stroke-neuroprotective-therapy-by-recombinant-activated-protein-c
#15
John H Griffin, Laurent O Mosnier, José A Fernández, Berislav V Zlokovic
APC (activated protein C), derived from the plasma protease zymogen, is antithrombotic and anti-inflammatory. In preclinical injury models, recombinant APC provides neuroprotection for multiple injuries, including ischemic stroke. APC acts directly on brain endothelial cells and neurons by initiating cell signaling that requires multiple receptors. Two or more major APC receptors mediate APC's neuroprotective cell signaling. When bound to endothelial cell protein C receptor, APC can cleave protease-activated receptor 1, causing biased cytoprotective signaling that reduces ischemia-induced injury...
November 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27624896/role-of-anterior-piriform-cortex-in-the-acquisition-of-conditioned-flavour-preference
#16
Cristina Mediavilla, Mar Martin-Signes, Severiano Risco
Flavour aversion learning (FAL) and conditioned flavour preference (CFP) facilitate animal survival and play a major role in food selection, but the neurobiological mechanisms involved are not completely understood. Neuroanatomical bases of CFP were examined by using Fos immunohistochemistry to record neuronal activity. Rats were trained over eight alternating one-bottle sessions to acquire a CFP induced by pairing a flavour with saccharin (grape was CS+ in Group 1; cherry in Group 2; in Group 3, grape/cherry in half of animals; Group 4, grape/cherry in water)...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27548576/3k3a-activated-protein-c-stimulates-postischemic-neuronal-repair-by-human-neural-stem-cells-in-mice
#17
Yaoming Wang, Zhen Zhao, Sanket V Rege, Min Wang, Gabriel Si, Yi Zhou, Su Wang, John H Griffin, Steven A Goldman, Berislav V Zlokovic
Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptor 1 (F2R, also known as PAR1) and F2RL1 (also known as PAR3) via noncanonical cleavage. Recombinant variants of APC, such as the 3K3A-APC (Lys191-193Ala) mutant in which three Lys residues (KKK191-193) were replaced with alanine, and/or its other mutants with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic and reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes and lethal body radiation...
September 2016: Nature Medicine
https://www.readbyqxmd.com/read/27514492/a%C3%AE-induces-excitotoxicity-mediated-by-apc-c-cdh1-depletion-that-can-be-prevented-by-glutaminase-inhibition-promoting-neuronal-survival
#18
T Fuchsberger, S Martínez-Bellver, E Giraldo, V Teruel-Martí, A Lloret, J Viña
The E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) is activated by the fizzy-related protein homolog/CDC20-like protein 1 (cdh1) in post-mitotic neurons. Growing evidence suggests that dysregulation of APC/C-Cdh1 is involved in neurodegenerative diseases. Here we show in neurons that oligomers of amyloid beta (Aβ), a peptide related to Alzheimer's disease, cause proteasome-dependent degradation of cdh1. This leads to a subsequent increase in glutaminase (a degradation target of APC/C-Cdh1), which causes an elevation of glutamate levels and further intraneuronal Ca(2+) dysregulation, resulting in neuronal apoptosis...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27312068/the-polyglutamine-expanded-androgen-receptor-responsible-for-spinal-and-bulbar-muscular-atrophy-inhibits-the-apc-c-cdh1-ubiquitin-ligase-complex
#19
Laura C Bott, Florian A Salomons, Dragan Maric, Yuhong Liu, Diane Merry, Kenneth H Fischbeck, Nico P Dantuma
Polyglutamine expansion in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA), an X-linked neuromuscular disease that is fully manifest only in males. It has been suggested that proteins with expanded polyglutamine tracts impair ubiquitin-dependent proteolysis due to their propensity to aggregate, but recent studies indicate that the overall activity of the ubiquitin-proteasome system is preserved in SBMA models. Here we report that AR selectively interferes with the function of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which, together with its substrate adaptor Cdh1, is critical for cell cycle arrest and neuronal architecture...
June 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27272132/tumour-suppressor-adenomatous-polyposis-coli-apc-localisation-is-regulated-by-both-kinesin-1-and-kinesin-2
#20
Peter T Ruane, Laura F Gumy, Becky Bola, Beverley Anderson, Marcin J Wozniak, Casper C Hoogenraad, Victoria J Allan
Microtubules and their associated proteins (MAPs) underpin the polarity of specialised cells. Adenomatous polyposis coli (APC) is one such MAP with a multifunctional agenda that requires precise intracellular localisations. Although APC has been found to associate with kinesin-2 subfamily members, the exact mechanism for the peripheral localization of APC remains unclear. Here we show that the heavy chain of kinesin-1 directly interacts with the APC C-terminus, contributing to the peripheral localisation of APC in fibroblasts...
2016: Scientific Reports
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