scholarly journals Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration

2013 ◽  
Vol 210 (12) ◽  
pp. 2553-2567 ◽  
Author(s):  
Christine D. Pozniak ◽  
Arundhati Sengupta Ghosh ◽  
Alvin Gogineni ◽  
Jesse E. Hanson ◽  
Seung-Hye Lee ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Leucine Zipper ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Receptor Activation ◽  
Scaffolding Protein ◽  
Glutamate Signaling ◽  
Postsynaptic Density Proteins ◽  
Primary Driver

Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid–induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss.

scholarly journals DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity

2011 ◽  
Vol 194 (5) ◽  
pp. 751-764 ◽  
Author(s):  
Arundhati Sengupta Ghosh ◽  
Bei Wang ◽  
Christine D. Pozniak ◽  
Mark Chen ◽  
Ryan J. Watts ◽  
...  
Keyword(s):  
Leucine Zipper ◽  
Neuronal Degeneration ◽  
Scaffolding Protein ◽  
Axon Degeneration ◽  
Jnk Signaling ◽  
Signaling Complex ◽  
Neuronal Populations ◽  
Neuronal Homeostasis ◽  
Stress Response Pathway

The c-Jun N-terminal kinase (JNK) signaling pathway is essential for neuronal degeneration in multiple contexts but also regulates neuronal homeostasis. It remains unclear how neurons are able to dissociate proapoptotic JNK signaling from physiological JNK activity. In this paper, we show that the mixed lineage kinase dual leucine zipper kinase (DLK) selectively regulates the JNK-based stress response pathway to mediate axon degeneration and neuronal apoptosis without influencing other aspects of JNK signaling. This specificity is dependent on interaction of DLK with the scaffolding protein JIP3 to form a specialized JNK signaling complex. Local activation of DLK-based signaling in the axon results in phosphorylation of c-Jun and apoptosis after redistribution of JNK to the cell body. In contrast, regulation of axon degeneration by DLK is c-Jun independent and mediated by distinct JNK substrates. DLK-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative DLK signaling is required in vivo.

scholarly journals Autophagy is Activated In Vivo during Trimethyltin-Induced Apoptotic Neurodegeneration: A Study in the Rat Hippocampus

2019 ◽  
Vol 21 (1) ◽  
pp. 175 ◽  
Author(s):  
Sabrina Ceccariglia ◽  
Alessandra Alvino ◽  
Aurora Del Fà ◽  
Ornella Parolini ◽  
Fabrizio Michetti ◽  
...  
Keyword(s):  
Western Blotting ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Organotin Compound ◽  
Nuclear Antigen ◽  
Apoptotic Pathway

Trimethyltin (TMT) is an organotin compound known to produce significant and selective neuronal degeneration and reactive astrogliosis in the rodent central nervous system. Autophagy is the main cellular mechanism for degrading and recycling protein aggregates and damaged organelles, which in different stress conditions, such as starvation, generally improves cell survival. Autophagy is documented in several pathologic conditions, including neurodegenerative diseases. This study aimed to investigate the autophagy and apoptosis signaling pathways in hippocampal neurons of TMT-treated (Wistar) rats to explore molecular mechanisms involved in toxicant-induced neuronal injury. The microtubule-associated protein light chain (LC3, autophagosome marker) and sequestosome1 (SQSTM1/p62) (substrate of autophagy-mediated degradation) expressions were examined by Western blotting at different time points after intoxication. The results demonstrate that the LC3 II/I ratio significantly increased at 3 and 5 days, and that p62 levels significantly decreased at 7 and 14 days. Immunofluorescence images of LC3/neuronal nuclear antigen (NeuN) showed numerous strongly positive LC3 neurons throughout the hippocampus at 3 and 5 days. The terminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL) assay indicated an increase in apoptotic cells starting from 5 days after treatment. In order to clarify apoptotic pathway, immunofluorescence images of apoptosis-inducing factor (AIF)/NeuN did not show nuclear translocation of AIF in neurons. Increased expression of cleaved Caspase-3 was revealed at 5–14 days in all hippocampal regions by Western blotting and immunohistochemistry analyses. These data clearly demonstrate that TMT intoxication induces a marked increase in both autophagy and caspase-dependent apoptosis, and that autophagy occurring just before apoptosis could have a potential role in neuronal loss in this experimental model of neurodegeneration.

Differential Activation of Glutamate Receptor Subtypes on a Single Class of Cells Enables a Neural Oscillator To Produce Distinct Behaviors

1997 ◽  
Vol 78 (2) ◽  
pp. 835-847 ◽  
Author(s):  
John E. Spiro
Keyword(s):  
Glutamate Receptor ◽  
Electric Organ Discharge ◽  
Receptor Activation ◽  
Neural Oscillator ◽  
Receptor Subtypes ◽  
Single Class ◽  
Differential Activation ◽  
Pacemaker Nucleus

Spiro, John E. Differential activation of glutamate receptor subtypes on a single class of cells enables a neural oscillator to produce distinct behaviors. J. Neurophysiol. 78: 835–847, 1997. Electric fish generate different types of abrupt modulations of their electric organ discharge (EOD) rhythm to convey specific social signals. Intracellular recordings were made from neurons of the medullary pacemaker nucleus, which generates and transmits the rhythm that drives the EOD, to study the neuronal basis of two such modulations of the regular EOD rhythm, sudden accelerations, and abrupt interruptions. Recordings were both in vivo, and in a new in vitro brain preparation of Hypopomus pinnicaudatus (order Gymnotiformes). In vivo recordings during triggered behaviors indicated that abrupt modulations of the EOD rhythm are generated in the medullary pacemaker nucleus at the level of the relay cells, which are the projection cells of the nucleus, and not the pacemaker cells. In the in vitro brain stem preparation, cells of the pacemaker nucleus were spontaneously and rhythmically active as in the intact animal. Distinct modulations of the pacemaker nucleus rhythm that closely resembled those seen during natural behaviors could be triggered by electrical stimulation of afferent fibers. Modulations of the rhythm also could be triggered by direct pharmacological activation of the relay cells. When non- N-methyl-d-aspartate (NMDA) receptors were activated, relay cells were transiently depolarized and generated bursts of synchronized action potentials. NMDA receptor activation, alternatively, initiated a prolonged depolarization in the relay cells, during which time they failedto relay the regular pacemaker rhythm. The two firing states ofthe relay cell directly correlate with sudden accelerations and abrupt interruptions of the EOD.

G protein coupling profile of mGluR6 and expression of Gα proteins in retinal ON bipolar cells

2006 ◽  
Vol 23 (6) ◽  
pp. 909-916 ◽  
Author(s):  
LIANTIAN TIAN ◽  
PAUL J. KAMMERMEIER
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Glutamate Receptor ◽  
Intracellular Signaling ◽  
Metabotropic Glutamate Receptor ◽  
Sympathetic Neurons ◽  
Photoreceptor Cells ◽  
Receptor Activation ◽  
Bipolar Cells

Metabotropic glutamate receptor 6 (mGluR6) is a group III, pertussis toxin (PTX)-sensitive G protein coupled mGluR that plays a specialized role in the retina. Retinal ON bipolar cells, which receive direct glutamatergic input from photoreceptor cells, express mGluR6 as their primary postsynaptic glutamate receptor. Activation of mGluR6 in these cells initiates an intracellular signaling cascade ultimately leading to inhibition of a cation channel and cell hyperpolarization. The primary mediator of this pathway in vivo is Gαo, but the potential roles of other G proteins from the Gαi/o family in the regulation of this or other signaling pathways in ON bipolar cells are unclear. To determine which specific G proteins from the Gαi/o family are able to couple to mGluR6, a Gα reconstitution system was employed using PTX-insensitive Gα mutants expressed with mGluR6 in PTX-treated sympathetic neurons from the rat superior cervical ganglion (SCG). The efficiency of coupling to mGluR6 was Goa > Gob, Gi1 > Gi2, Gi3, whereas no coupling was observed with Gαz, nor with the retinal Gα proteins, rod (GNAT2) or cone (GNAT1) transducin (GαTr-R, GαTr-C). Finally, the expression of Gα proteins determined to couple with mGluR6 was examined in rat ON bipolar cells using single cell RT-PCR. Co-expression of mGluR6 message was used to distinguish ON from OFF bipolar cells. Expression of Gαo was detected in every ON bipolar cell examined. Message for Gαi1, which coupled moderately to mGluR6, was not detected in ON bipolar cells, nor was Gαi3, which coupled to mGluR6 in only a few cells but on average did not exhibit statistically significant coupling. Finally, though Gαi2 was detectable in ON bipolar cells, its coupling to mGluR6 in the SCG system was not significant. Together, these data indicate that signaling through mGluR6 in mammalian ON bipolar cells is highly focused, apparently acting through a single Gα protein subtype.

scholarly journals Forced Dimerization of gp130 Leads to Constitutive STAT3 Activation, Cytokine-independent Growth, and Blockade of Differentiation of Embryonic Stem Cells

2006 ◽  
Vol 17 (7) ◽  
pp. 2986-2995 ◽  
Author(s):  
Christiane Stuhlmann-Laeisz ◽  
Sigrid Lang ◽  
Athena Chalaris ◽  
Paliga Krzysztof ◽  
Sudarman Enge ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Leucine Zipper ◽  
Signal Transmission ◽  
Embryonic Stem ◽  
Constitutive Expression ◽  
Receptor Activation ◽  
Receptor Protein

The mode of activation of glycoprotein 130 kDa (gp130) and the transmission of the activation status through the plasma membrane are incompletely understood. In particular, the molecular function of the three juxtamembrane fibronectin III-like domains of gp130 in signal transmission remains unclear. To ask whether forced dimerization of gp130 is sufficient for receptor activation, we replaced the entire extracellular portion of gp130 with the c-jun leucine zipper region in the chimeric receptor protein L-gp130. On expression in cells, L-gp130 stimulates ligand-independent signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase 1/2 phosphorylation. gp130 activation could be abrogated by the addition of a competing peptide comprising the leucine zipper region of c-fos. When stably expressed in the interleukin-3–dependent Ba/F3 murine pre-B-cells, these cells showed constitutive STAT3 activation and cytokine-independent growth over several months. Because gp130 stimulation completely suppressed differentiation of murine embryonic stem cells in vitro, we also stably expressed L-gp130 in these cells, which completely blocked their differentiation in the absence of cytokine stimulation and was consistent with high constitutive expression levels of the stem cell factor OCT-4. Thus, L-gp130 can be used in vitro and in vivo to mimic constitutive and ligand-independent activation of gp130 and STAT3, the latter of which is frequently observed in neoplastic diseases.

In vivo evaluation of [11C]CNS-5161 as a use-dependent ligand for the NMDA glutamate receptor channel

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S595-S595 ◽  
Author(s):  
Wynne K Schiffer ◽  
Deborah Pareto-Onghena ◽  
HaiTao Wu ◽  
Kuo-Shyan Lin ◽  
Andrew R Gibbs ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
In Vivo Evaluation ◽  
Nmda Glutamate Receptor ◽  
Receptor Channel
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