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Apc and neuron

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...
October 6, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
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
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
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
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...
2016: Scientific Reports
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
Rongfeng Hu, Juen Zhang, Minmin Luo, Ji Hu
Local inhibition by γ-amino butyric acid (GABA)-containing neurons is of vital importance for the operation of sensory cortices. However, the physiological response patterns of cortical GABAergic neurons are poorly understood, especially in the awake condition. Here, we utilized the recently developed optical tagging technique to specifically record GABAergic neurons in the anterior piriform cortex (aPC) in awake mice. The identified aPC GABAergic neurons were stimulated with robotic delivery of 32 distinct odorants, which covered a broad range of functional groups...
June 1, 2016: Cerebral Cortex
Julia Wang, Alexandra K Jennings, Jennifer R Kowalski
The regulation of fundamental aspects of neurobiological function has been linked to the ubiquitin signaling system (USS), which regulates the degradation and activity of proteins and is catalyzed by E1, E2, and E3 enzymes. The Anaphase-Promoting Complex (APC) is a multi-subunit E3 ubiquitin ligase that controls diverse developmental and signaling processes in post-mitotic neurons; however, potential roles for the APC in sensory function have yet to be explored. In this study, we examined the effect of the APC ubiquitin ligase on chemosensation in Caenorhabditis elegans by testing chemotaxis to the volatile odorants, diacetyl, pyrazine, and isoamyl alcohol, to which wild-type worms are attracted...
2016: PeerJ
Rong Hu, Li Li, Dajia Li, Wei Tan, Li Wan, Chang Zhu, Yue Zhang, Chuanhan Zhang, Wenlong Yao
BACKGROUND: Anaphase-promoting complex/cyclosome (APC/C) and its co-activator Cdh1 are important ubiquitin-ligases in proliferating cells and terminally differentiated neurons. In recent years, APC/C-Cdh1 has been reported as an important complex contributing to synaptic development and transmission. Interestingly, cortical APC/C-Cdh1 is found to play a critical role in the maintenance of neuropathic pain, but it is not clear whether APC/C-Cdh1 in spinal dorsal cord is involved in molecular mechanisms of neuropathic pain conditions...
2016: Molecular Pain
Samantha L Hersrud, Attila D Kovács, David A Pearce
Mutations of the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive lysosomal storage disorder that causes progressive neurodegeneration in children and adolescents. There is evidence of immune system involvement in pathology that has been only minimally investigated. We characterized bone marrow stem cell-derived antigen presenting cells (APCs), peritoneal macrophages, and leukocytes from spleen and blood, harvested from the Cln3(-/-) mouse model of JNCL. We detected dramatically elevated CD11c surface levels and increased total CD11c protein in Cln3(-/-) cell samples compared to wild type...
July 2016: Biochimica et Biophysica Acta
Chris Chambers, Ian Witton, Cathryn Adams, Luke Marrington, Juha Kammonen
Voltage-gated sodium (Na(V)) channels have an essential role in the initiation and propagation of action potentials in excitable cells, such as neurons. Of these channels, Na(V)1.7 has been indicated as a key channel for pain sensation. While extensive efforts have gone into discovering novel Na(V)1.7 modulating compounds for the treatment of pain, none has reached the market yet. In the last two years, new compound screening technologies have been introduced, which may speed up the discovery of such compounds...
March 2016: Assay and Drug Development Technologies
Felix Lüssi, Frauke Zipp, Esther Witsch
Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disorder of the central nervous system characterized by infiltration of immune cells and progressive damage to myelin sheaths and neurons. There is still no cure for the disease, but drug regimens can reduce the frequency of relapses and slightly delay progression. Myeloid cells or antigen-presenting cells (APCs) such as dendritic cells (DC), macrophages, and resident microglia, are key players in both mediating immune responses and inducing immune tolerance...
July 2016: Cellular and Molecular Life Sciences: CMLS
Juan P Bolaños
Neuronal activity is a high-energy demanding process recruiting all neural cells that adapt their metabolism to sustain the energy and redox balance of neurons. During neurotransmission, synaptic cleft glutamate activates its receptors in neurons and in astrocytes, before being taken up by astrocytes through energy costly transporters. In astrocytes, the energy requirement for glutamate influx is likely to be met by glycolysis. To enable this, astrocytes are constitutively glycolytic, robustly expressing 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), an enzyme that is negligibly present in neurons by continuous degradation because of the ubiquitin-proteasome pathway via anaphase-promoting complex/cyclosome (APC)-Cdh1...
March 10, 2016: Journal of Neurochemistry
C R Zaccard, C R Rinaldo, R B Mailliard
Membrane nanotubes, also termed tunneling nanotubes, are F-actin-based structures that can form direct cytoplasmic connections and support rapid communication between distant cells. These nanoscale conduits have been observed in diverse cell types, including immune, neuronal, stromal, cancer, and stem cells. Until recently, little was known about the mechanisms involved in membrane nanotube development in myeloid origin APCs or how membrane nanotube networks support their ability to bridge innate and adaptive immunity...
July 2016: Journal of Leukocyte Biology
Kuo-Mao Lan, Lu-Tai Tien, Zhengwei Cai, Shuying Lin, Yi Pang, Sachiko Tanaka, Philip G Rhodes, Abhay J Bhatt, Renate D Savich, Lir-Wan Fan
The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)-P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult...
2016: International Journal of Molecular Sciences
Ranjeet K Sinha, Xia V Yang, José A Fernández, Xiao Xu, Laurent O Mosnier, John H Griffin
OBJECTIVE: Activated protein C (APC), a plasma serine protease, initiates cell signaling that protects endothelial cells from apoptosis and endothelial barrier disruption. Apolipoprotein E receptor 2 (ApoER2; LRP8) is a receptor known for mediating signaling initiated by reelin in neurons. ApoER2 contributes to APC-initiated signaling in monocytic U937 cells. The objective was to determine whether ApoER2 is required for APC's beneficial signaling in the endothelial cell surrogate EA.hy926 line...
March 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Alexis T Weiner, Michael C Lanz, Daniel J Goetschius, William O Hancock, Melissa M Rolls
In Drosophila neurons, kinesin-2, EB1 and Apc are required to maintain minus-end-out dendrite microtubule polarity, and we previously proposed they steer microtubules at branch points. Motor-mediated steering of microtubule plus ends could be accomplished in two ways: 1) by linking a growing microtubule tip to the side of an adjacent microtubule as it navigates the branch point (bundling), or 2) by directing a growing microtubule after a collision with a stable microtubule (collision resolution). Using live imaging to distinguish between these two mechanisms, we found that reduction of kinesin-2 did not alter the number of microtubules that grew along the edge of the branch points where stable microtubules are found...
January 2016: Cytoskeleton
Johnny D Figueroa, Miguel Serrano-Illan, Jenniffer Licero, Kathia Cordero, Jorge D Miranda, Marino De Leon
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) promote functional recovery in rats undergoing spinal cord injury (SCI). However, the precise molecular mechanism coupling n-3 PUFAs to neurorestorative responses is not well understood. The aim of the present study was to determine the spatiotemporal expression of fatty acid binding protein 5 (FABP5) after contusive SCI and to investigate whether this protein plays a role in n-3 PUFA-mediated functional recovery post-SCI. We found that SCI resulted in a robust spinal cord up-regulation in FABP5 mRNA levels (556 ± 187%) and protein expression (518 ± 195%), when compared to sham-operated rats, at 7 days post-injury (dpi)...
August 1, 2016: Journal of Neurotrauma
Miguel Veas-Pérez de Tudela, Carolina Maestre, María Delgado-Esteban, Juan P Bolaños, Angeles Almeida
The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that regulates cell cycle progression in proliferating cells. To enter the S-phase, APC/C must be inactivated by phosphorylation of its cofactor, Cdh1. In post-mitotic cells such as neurons APC/C-Cdh1 complex is highly active and responsible for the continuous degradation of mitotic cyclins. However, the specific molecular pathway that determines neuronal cell cycle blockade in post-mitotic neurons is unknown. Here, we show that activation of glutamatergic receptors in rat cortical primary neurons endogenously triggers cyclin-dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1 leading to its cytoplasmic accumulation and disassembly from the APC3 core protein, causing APC/C inactivation...
2015: Scientific Reports
Julian M C Choy, Norimitsu Suzuki, Yasuyuki Shima, Timotheus Budisantoso, Sacha B Nelson, John M Bekkers
Despite its comparatively simple trilaminar architecture, the primary olfactory (piriform) cortex of mammals is capable of performing sophisticated sensory processing, an ability that is thought to depend critically on its extensive associational (intracortical) excitatory circuits. Here, we used a novel transgenic mouse model and optogenetics to measure the connectivity of associational circuits that originate in semilunar (SL) cells in layer 2a of the anterior piriform cortex (aPC). We generated a mouse line (48L) in which channelrhodopsin-2 (ChR) could be selectively expressed in a subset of SL cells...
October 26, 2015: Cerebral Cortex
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