• MeSH
• fosfoproteiny metabolismus   MeSH
• neurony fyziologie   MeSH
• Publikační typ
• kongresy MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• neurovědy

Peripheral nerve injury results in profound alterations of the affected neurons resulting from the interplay between intrinsic and extrinsic molecular events. Restarting the neuronal regenerative program is an important prerequisite for functional recovery of the injured peripheral nerve. The primary sensory neurons with their cell bodies in the dorsal root ganglia provide a useful in vivo and in vitro model for studying the mechanisms that regulate intrinsic neuronal regeneration capacity following axotomy. These studies frequently need to indicate the regenerative status of the corresponding neurons. We summarize the critical issues regarding immunohistochemical detection of several regeneration-associated proteins as markers for the initiation of the regeneration program in rat primary sensory neurons and indicators of axon regeneration in the peripheral nerves. This overview also includes our own results of GAP43 and SCG10 expression in different DRG neurons following double immunostaining with molecular markers of neuronal subpopulations (NF200, CGRP, and IB4) as well as transcription factors (ATF3 and activated STAT3) following unilateral sciatic nerve injury. Anat Rec, 301:1618-1627, 2018. © 2018 Wiley Periodicals, Inc.

• MeSH
• axony metabolismus   MeSH
• biologické markery metabolismus   MeSH
• fyziologický stres MeSH
• korneocytární obal - proteiny bohaté na prolin metabolismus   MeSH
• membránové proteiny metabolismus   MeSH
• mikrotubulární proteiny MeSH
• nervové receptory klasifikace   fyziologie   MeSH
• protein GAP-43 metabolismus   MeSH
• regenerace nervu * MeSH
• spinální ganglia cytologie   metabolismus   MeSH
• transportní proteiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• chování MeSH
• molekulární biologie MeSH
• nemoci nervového systému MeSH
• nervový systém MeSH
• neurochemie MeSH
• neurofyziologie MeSH
• neurony MeSH
• neurovědy MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Fyziologie člověka a srovnávací fyziologie
• NLK Obory
• neurovědy
• biologie

Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases.

• MeSH
• alternativní sestřih MeSH
• Alzheimerova nemoc metabolismus   patologie   MeSH
• amyotrofická laterální skleróza metabolismus   patologie   MeSH
• astrocyty cytologie   účinky léků   metabolismus   MeSH
• autofagie účinky léků   MeSH
• genetické vektory genetika   metabolismus   MeSH
• interleukin-6 genetika   metabolismus   MeSH
• kokultivační techniky MeSH
• kultivované buňky MeSH
• leupeptiny farmakologie   MeSH
• lidé MeSH
• malá interferující RNA metabolismus   MeSH
• mozek metabolismus   patologie   MeSH
• nádorový supresorový protein p53 antagonisté a inhibitory   genetika   metabolismus   MeSH
• neurony cytologie   metabolismus   MeSH
• neuroprotekce fyziologie   MeSH
• protein - isoformy antagonisté a inhibitory   genetika   metabolismus   MeSH
• RNA interference MeSH
• sekvestosom 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• serin-arginin sestřihové faktory antagonisté a inhibitory   genetika   metabolismus   MeSH
• stárnutí buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The Slack (KCNT1) gene encodes sodium-activated potassium channels that are abundantly expressed in the central nervous system. Human mutations alter the function of Slack channels, resulting in epilepsy and intellectual disability. Most of the disease-causing mutations are located in the extended cytoplasmic C-terminus of Slack channels and result in increased Slack current. Previous experiments have shown that the C-terminus of Slack channels binds a number of cytoplasmic signaling proteins. One of these is Phactr1, an actin-binding protein that recruits protein phosphatase 1 (PP1) to certain phosphoprotein substrates. Using co-immunoprecipitation, we found that Phactr1 is required to link the channels to actin. Using patch clamp recordings, we found that co-expression of Phactr1 with wild-type Slack channels reduces the current amplitude but has no effect on Slack channels in which a conserved PKC phosphorylation site (S407) that regulates the current amplitude has been mutated. Furthermore, a Phactr1 mutant that disrupts the binding of PP1 but not that of actin fails to alter Slack currents. Our data suggest that Phactr1 regulates the Slack by linking PP1 to the channel. Targeting Slack-Phactr1 interactions may therefore be helpful in developing the novel therapies for brain disorders associated with the malfunction of Slack channels.

• MeSH
• aktiny metabolismus   MeSH
• buněčné linie MeSH
• draslíkové kanály aktivované sodíkem metabolismus   MeSH
• HEK293 buňky MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• membránové potenciály fyziologie   MeSH
• metoda terčíkového zámku metody   MeSH
• mutace genetika   MeSH
• myši MeSH
• neurony metabolismus   MeSH
• proteinfosfatasa 1 metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

In mature neurons, postsynaptic N-methyl-D-aspartate receptors (NMDARs) are segregated into two populations, synaptic and extrasynaptic, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content. Here, we identify the phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (at S1480) as a critical determinant in dynamically controlling NMDAR synaptic content. We find that phosphorylation of GluN2B at S1480 maintains NMDARs at extrasynaptic membranes as part of a protein complex containing protein phosphatase 1 (PP1). Global activation of NMDARs leads to the activation of PP1, which mediates dephosphorylation of GluN2B at S1480 to promote an increase in synaptic NMDAR content. Thus, PP1-mediated dephosphorylation of the GluN2B PDZ-ligand modulates the synaptic expression of NMDARs in mature neurons in an activity-dependent manner, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission.

• MeSH
• fosforylace MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• ligandy MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neurony metabolismus   MeSH
• PDZ domény MeSH
• potkani Sprague-Dawley MeSH
• proteinfosfatasa 1 metabolismus   MeSH
• receptory N-methyl-D-aspartátu genetika   metabolismus   MeSH
• synapse metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Low-voltage-activated T-type calcium channels are essential contributors to the functioning of thalamocortical neurons by supporting burst-firing mode of action potentials. Enhanced T-type calcium conductance has been reported in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and proposed to be causally related to the overall development of absence seizure activity. Here, we show that calnexin, an endoplasmic reticulum integral membrane protein, interacts with the III-IV linker region of the Cav3.2 channel to modulate the sorting of the channel to the cell surface. We demonstrate that the GAERS missense mutation located in the Cav3.2 III-IV linker alters the Cav3.2/calnexin interaction, resulting in an increased surface expression of the channel and a concomitant elevation in calcium influx. Our study reveals a novel mechanism that controls the expression of T-type channels, and provides a molecular explanation for the enhancement of T-type calcium conductance in GAERS.

• MeSH
• absentní epilepsie genetika   MeSH
• kalnexin metabolismus   MeSH
• krysa rodu rattus MeSH
• missense mutace * MeSH
• modely nemocí na zvířatech MeSH
• mutantní proteiny genetika   metabolismus   MeSH
• transport proteinů MeSH
• vápníkové kanály - typ T genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH