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tisdag 17 december 2019

RPH3A (12q24.13) , RABPHILIN 3A , exofiliini-1, ( 133 artikkelia)

https://www.ncbi.nlm.nih.gov/pubmed/?term=Rabphilin+3A

Haku: Geeni Rabphilin 3A  ( Huom.  luin tmän proteiinin olemassaolosta vasta eilen 16.12.2019)

Official Symbol
RPH3Aprovided by HGNC
Official Full Name
rabphilin 3Aprovided by HGNC
Summary
The protein encoded by this gene is thought to be an effector for RAB3A, which is a small G protein that acts in the late stages of neurotransmitter exocytosis. The encoded protein may be involved in neurotransmitter release and synaptic vesicle traffic. [provided by RefSeq, Dec 2016]
Expression
Biased expression in brain (RPKM 30.1) and adrenal (RPKM 1.7) See more
Orthologs
Preferred Names
rabphilin-3A
Names
exophilin-1
rabphilin 3A homolog










Genomic context

See RPH3A in Genome Data Viewer
Location:
12q24.13
Exon count:
27
https://www.ncbi.nlm.nih.gov/protein/NP_001137326.1


Conserved Domains (3) summary
cd04035
Location:393516
C2A_Rabphilin_Doc2; C2 domain first repeat present in Rabphilin and Double C2 domain ( Ca2++ binding  domain)
cd08384
Location:553685
C2B_Rabphilin_Doc2; C2 domain second repeat present in Rabphilin and Double C2 domain
(C2 domain second repeat present in Rabphilin and Double C2 domain
Rabphilin is found neurons and in neuroendrocrine cells, while Doc2 is found not only in the brain but in tissues, including mast cells, chromaffin cells, and osteoblasts. Rabphilin and Doc2s share highly homologous tandem C2 domains, although their N-terminal structures are completely different: rabphilin contains an N-terminal Rab-binding domain (RBD),7 whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.
cd15762
Location:92171
FYVE_RP3A; FYVE-related domain found in rabphilin-3A and similar proteins

FYVE-related domain found in rabphilin-3A and similar proteins
Rabphilin-3A, also termed exophilin-1, is an effector protein that binds to the GTP-bound form of Rab3A, which is one of the most abundant Rab proteins in neurons and predominantly localized to synaptic vesicles. Rabphilin-3A is homologous to alpha-Rab3-interacting molecules (RIMs). It is a multi-domain protein containing an N-terminal Rab3A effector domain, a proline-rich linker region, and two tandem C2 domains. The effector domain binds specifically to the activated GTP-bound state of Rab3A and harbors a conserved FYVE zinc finger. The C2 domains are responsible for the binding of phosphatidylinositol-4,5-bisphosphate (PIP2) , a key player in the neurotransmitter release process. Thus, Rabphilin-3A has also been implicated in vesicle trafficking. The FYVE domain of Rabphilin-3A resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif.
Feature 1: Zn binding site [ion binding site], 8 residue positions
Conserved feature residue pattern:C C C C C C C CClick to see conserved feature residue pattern help
Evidence:
  • Structure:1ZBD; Rattus norvegicus Rabphilin-3A binds two Zn2+ through its effector domain.
    View structure with Cn3D
  • Citation:PMID 10025402
ite            order(98,101,115,118,123,126,140,143)
                     /site_type="other"
                     /note="Zn binding site [ion binding]"
                     /db_xref="CDD:277301"

ORIGIN      
        1 mtdtvfsnss nrwmypsdrp lqsndkeqlq agwsvhpggq pdrqrkqeel tdeekeiinr
       61 viaraekmee meqerigrlv drlenmrknv agdgvnrCil Cgeqlgmlgs acvvCedCkk
      121 nvCtkCgvet nnrlhsvwlC kiCieqrevw krsgawffkg fpkqvlpqpm pikktkpqqp
      181 vsepaapeqp apepkhpara pargdsedrr gpgqktgpdp asapgrgnyg ppvrrasear
      241 mssssrdses wdhsggagds srspaglrra nsvqasrpap gsvqspappq pgqpgtpggs
      301 rpgpgpagrf pdqkpevaps dpgttappre ertggvggyp avgaredrms hpsgpysqas
      361 aaapqpaaar qppppeeeee eansydsdea ttlgalefsl lydqdnsslq ctiikakglk
      421 pmdsngladp yvklhllpga sksnklrtkt lrntrnpiwn etlvyhgitd edmqrktlri
      481 svcdedkfgh nefigetrfs lkklkpnqrk nfniclervi pmkragttgs argmalyeee
      541 qvervgdiee rgkilvslmy stqqgglivg iircvhlaam dangysdpfv klwlkpdmgk
      601 kakhktqikk ktlnpefnee ffydikhsdl akksldisvw dydigksndy iggcqlgisa
      661 kgerlkhwye clknkdkkie rwhqlqnenh vssd
//


4.
Del Arroyo AG, Hadjihambi A, Sanchez J, Turovsky E, Kasymov V, Cain D, Nightingale TD, Lambden S, Grant SGN, Gourine AV, Ackland GL.
EBioMedicine. 2019 Sep;47:457-469. doi: 10.1016/j.ebiom.2019.08.004. Epub 2019 Aug 8.
NMDA receptor (NMDAR) subunit composition plays a pivotal role in synaptic plasticity at excitatory synapses. Still, the mechanisms responsible for the synaptic retention of NMDARs following induction of plasticity need to be fully elucidated. Rabphilin3A (Rph3A) is involved in the stabilization of NMDARs at synapses through the formation of a complex with GluN2A and PSD-95. Here we used different protocols to induce synaptic plasticity in the presence or absence of agents modulating Rph3A function. The use of Forskolin/Rolipram/Picrotoxin cocktail to induce chemical LTP led to synaptic accumulation of Rph3A and formation of synaptic GluN2A/Rph3A complex. Notably, Rph3A silencing or use of peptides interfering with the GluN2A/Rph3A complex blocked LTP induction. Moreover, in vivo disruption of GluN2A/Rph3A complex led to a profound alteration of spatial memory. Overall, our results demonstrate a molecular mechanism needed for NMDAR stabilization at synapses after plasticity induction and to trigger downstream signaling events necessary for cognitive behavior.Free PMC Article
Similar articles


katsottava yhteys Ach erg. neurons,rabphilin3A?

2014 Jan;64:29-36. doi: 10.1016/j.neuint.2013.10.013. Epub 2013 Nov 5.

Decreased rabphilin 3A immunoreactivity in Alzheimer's disease is associated with Aβ burden.


Abstract
Synaptic dysfunction, together with neuritic plaques, neurofibrillary tangles and cholinergic neuron loss is an established finding in the Alzheimer's disease (AD) neocortex. The synaptopathology of AD is known to involve both pre- and postsynaptic components. However, the status of rabphilin 3A (RPH3A), which interacts with the SNARE complex and regulates synaptic vesicle exocytosis and Ca(2+)-triggered neurotransmitter release, is at present unclear. In this study, we measured RPH3A and its ligand Rab3A as well as several SNARE proteins in postmortem neocortex of patients with AD, and found specific reductions of RPH3A immunoreactivity compared with aged controls. RPH3A loss correlated with dementia severity, cholinergic deafferentation, and increased β-amyloid (Aβ) concentrations. Furthermore, RPH3A expression is selectively downregulated in cultured neurons treated with Aβ25-35 peptides. Our data suggest that presynaptic SNARE dysfunction forms part of the synaptopathology of AD.

NMDA reseptorin stabiliteetti ja USP6 (DUB) deubikitinaasi

Hakusana: Ubiquitylation of PSD-95?
Vastausartikkeli: https://www.ncbi.nlm.nih.gov/pubmed/31841517

2019 Dec 16;17(12):e3000525. doi: 10.1371/journal.pbio.3000525. eCollection 2019 Dec.

The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability.

1
State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.
2
School of Life Sciences, Xinjiang Normal University, Urumqi, China.
3
Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing, China.
4
School of Biomedical Sciences, Huaqiao University, Quanzhou, China.
5
Department of Neurosurgery, the First Affiliated Hospital of Xiamen University, Xiamen, China.
6
Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
7
Department of Functional Neurosurgery, Xiamen Humanity Hospital, Xiamen, China.
8
Department of Translational Medicine, School of Medicine, Xiamen University, Xiamen, China.
9
Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.

Abstract

Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme (DUB) previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD)in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition.
PMID:
31841517
DOI:
10.1371/journal.pbio.3000525

 

måndag 16 december 2019

HAKU: PSD-95 (AND) NMDAr

See Gene information for nmdar psd95

Search results

Items: 1 to 20 of 563

1.
Xie J, Jusuf PR, Bui BV, Goodbourn PT.
Sci Rep. 2019 Dec 12;9(1):18931. doi: 10.1038/s41598-019-54958-6.
2.
Murciano-Calles J, Coello A, Cámara-Artigas A, Martinez JC.
J Mol Recognit. 2019 Nov 19:e2826. doi: 10.1002/jmr.2826. [Epub ahead of print]
N-Methyl-D-aspartate (NMDA) receptors are key components in synaptic communication and are highly relevant in central nervous disorders, where they trigger excessive calcium entry into the neuronal cells causing harmful overproduction of nitric oxide by the neuronal nitric oxide synthase (nNOS) protein. Remarkably, NMDA receptor activation is aided by a second protein, postsynaptic density of 95 kDa (PSD95), forming the ternary protein complex NMDA/PSD95/nNOS. To minimize the potential side effects derived from blocking this ternary complex or either of its protein components, a promising approach points to the disruption of the PSD-95/nNOS interaction which is mediated by a PDZ/PDZ domain complex. Since the rational development of molecules targeting such protein-protein interaction relies on energetic and structural information herein, we include a thermodynamic and structural analysis of the PSD95-PDZ2/nNOS-PDZ. Two energetically relevant events are structurally linked to a "two-faced" or two areas of recognition between both domains. First, the assembly of a four-stranded antiparallel β-sheet between the β hairpins of nNOS and of PSD95-PDZ2, mainly enthalpic in nature, contributes 80% to the affinity. Second, binding is entropically reinforced by the hydrophobic interaction between side chains of the same nNOS β-hairpin with the side chains of α2-helix at the binding site of PSD95-PDZ2, contributing the remaining 20% of the total affinity. These results suggest strategies for the future rational design of molecules able to disrupt this complex and constitute the first exhaustive thermodynamic analysis of a PDZ/PDZ interaction.
3.
Franchini L, Stanic J, Ponzoni L, Mellone M, Carrano N, Musardo S, Zianni E, Olivero G, Marcello E, Pittaluga A, Sala M, Bellone C, Racca C, Di Luca M, Gardoni F.
iScience. 2019 Sep 27;19:927-939. doi: 10.1016/j.isci.2019.08.036. Epub 2019 Aug 27.
4.
Del Arroyo AG, Hadjihambi A, Sanchez J, Turovsky E, Kasymov V, Cain D, Nightingale TD, Lambden S, Grant SGN, Gourine AV, Ackland GL.
EBioMedicine. 2019 Sep;47:457-469. doi: 10.1016/j.ebiom.2019.08.004. Epub 2019 Aug 8.
NMDA receptor (NMDAR) subunit composition plays a pivotal role in synaptic plasticity at excitatory synapses. Still, the mechanisms responsible for the synaptic retention of NMDARs following induction of plasticity need to be fully elucidated. Rabphilin3A (Rph3A) is involved in the stabilization of NMDARs at synapses through the formation of a complex with GluN2A and PSD-95. Here we used different protocols to induce synaptic plasticity in the presence or absence of agents modulating Rph3A function. The use of Forskolin/Rolipram/Picrotoxin cocktail to induce chemical LTP led to synaptic accumulation of Rph3A and formation of synaptic GluN2A/Rph3A complex. Notably, Rph3A silencing or use of peptides interfering with the GluN2A/Rph3A complex blocked LTP induction. Moreover, in vivo disruption of GluN2A/Rph3A complex led to a profound alteration of spatial memory. Overall, our results demonstrate a molecular mechanism needed for NMDAR stabilization at synapses after plasticity induction and to trigger downstream signaling events necessary for cognitive behavior.Free PMC Article
5.
Bowers MS, Cacheaux LP, Sahu SU, Schmidt ME, Sennello JA, Leaderbrand K, Khan MA, Kroes RA, Moskal JR.
J Neurochem. 2019 Aug 3. doi: 10.1111/jnc.14845. [Epub ahead of print]
PMID:
31376158
6.
Warming H, Pegasiou CM, Pitera AP, Kariis H, Houghton SD, Kurbatskaya K, Ahmed A, Grundy P, Vajramani G, Bulters D, Altafaj X, Deinhardt K, Vargas-Caballero M.
Mol Brain. 2019 Jul 4;12(1):64. doi: 10.1186/s13041-019-0485-9.
Glutamate receptors of the N-methyl-D-aspartate (NMDA) family are coincident detectors of pre- and postsynaptic activity, allowing Ca2+ influx into neurons. These properties are central to neurological disease mechanisms and are proposed to be the basis of associative learning and memory. In addition to the well-characterised canonical GluN2A NMDAR isoform, large-scale open reading frames in human tissues had suggested the expression of a primate-specific short GluN2A isoform referred to as GluN2A-S. Here, we confirm the expression of both GluN2A transcripts in human and primate but not rodent brain tissue, and show that they are translated to two corresponding GluN2A proteins present in human brain. Furthermore, we demonstrate that recombinant GluN2A-S co-assembles with the obligatory NMDAR subunit GluN1 to form functional NMDA receptors. These findings suggest a more complex NMDAR repertoire in human brain than previously thought.
Introduction
NMDA receptors are activated by coincident glutamate binding and intracellular depolarisation. Ca2+ entry via NMDARs can gate long-term biochemical and gene expression changes that alter synaptic strength, which are proposed as central to mechanisms of memory storage [17] and neurodegenerative processes [9]. Our current knowledge of NMDAR function is largely derived from the study of rodent receptors and heterologous expression of cloned rodent genes. Tetrameric NMDARs comprise two obligatory GluN1 subunits and two GluN2 or GluN3 subunits, and in the adult forebrain GluN1/GluN2A, GluN1/GluN2B diheteromers, and GluN1/GluN2A/GluN2B triheteromers are the most common [18, 19]. The subunit combination confers the distinct biophysical and pharmacological properties to the receptor channel. The developmentally and anatomically regulated gene expression of NMDAR subunits, together with diverse post-translational modification mechanisms and protein interactions, determines the assembly, trafficking, synaptic or extrasynaptic localisation and internalisation of NMDARs (Reviewed in [16]) and their correct functioning is necessary for human brain functions [5, 6, 21].
Homologous rodent and human NMDARs do share highly conserved subunit sequences and exhibit almost identical pharmacological properties [10]. However, large scale open reading frame studies performed with mRNA from a mix of human tissues [20, 28] have suggested that in addition to the conserved NMDAR canonical isoform of GluN2A in chordates, a shorter isoform is produced in humans (GluN2A-S) generated by alternative splicing of human GRIN2A (Fig. 1a). Here, we show that this alternative NMDAR isoform is expressed in the human and primate brain, and that it forms functional receptors together with the obligatory subunit GluN1 [15]. The presence of alternative NMDAR subunits not expressed in rodent model systems indicates the existence of unexplored neural mechanisms in human synapses with relevance to normal function, ageing and neurological disease....
Here we describe for the first time the brain expression of an uncharacterised, primate-specific NMDAR subunit. The splice site for GluN2A-S suggests that it will contain a diverging 19 aa sequence in its extreme C-terminal domain (Fig. 2a), in addition to lacking the distal carboxy terminal domain (183 amino acids) that contains PKC/SFK phosphorylation sites, two PDZ binding motifs that allow synaptic localisation [4, 12, 14], and a dileucin clathrin adaptor motif involved in receptor internalisation [13]. Following many lines of published evidence, these differences suggest that the dynamic regulation of GluN2A-S in response to stimuli could diverge from GluN2A subunit-containing NMDARs. This could impact the number of receptors present synaptically or extrasynaptically, the insertion of new receptors into the membrane, their lateral diffusion and clustering into synapses and their active removal. The potential changes in human synapses compared to mouse neurons void of GluN2A-S could result in distinct mechanisms involved in activity-dependent plasticity of synapses, which will highly depend upon its triheteromeric partners [1, 8, 19].
...Together, our data suggest that GluN2A-S is a primate-specific NMDAR subunit and a substantial component of functional NMDARs in the adult human brain. Many neuronal mechanisms discovered in mice have been successfully recapitulated in humans. However, mounting evidence suggests that there are important differences between rodent and human neurons that result in distinct signal integration properties [22, 23, 26] and proteomic composition of synapses [3]. Species differences may ultimately impact the way in which human neural circuits can be computationally modelled [7], and the translation of pre-clinical findings into approved therapies [24]. Further analyses of GluN2A-S spatio-temporal gene expression and synaptic/ extrasynaptic localisation will enhance our knowledge of their functional role and may uncover NMDAR trafficking mechanisms present only in primates and diverging sequences may uncover novel therapeutic targets.
Free PMC Article
7.
Coley AA, Gao WJ.
Sci Rep. 2019 Jul 1;9(1):9486. doi: 10.1038/s41598-019-45971-w.
8.
Luo P, Li X, Wu X, Dai S, Yang Y, Xu H, Jing D, Rao W, Xu H, Gao X, Fei Z, Lu H.
Cell Death Dis. 2019 Jun 24;10(7):496. doi: 10.1038/s41419-019-1731-x.
9.
Levy NS, Umanah GKE, Rogers EJ, Jada R, Lache O, Levy AP.
Int J Mol Sci. 2019 Jun 21;20(12). pii: E3038. doi: 10.3390/ijms20123038. Review.
10.
Lee H, Shin W, Kim K, Lee S, Lee EJ, Kim J, Kweon H, Lee E, Park H, Kang M, Yang E, Kim H, Kim E.
PLoS Biol. 2019 Jun 5;17(6):e2005326. doi: 10.1371/journal.pbio.2005326. eCollection 2019 Jun.
11.
Wang H, Zhao P, Huang Q, Chi Y, Dong S, Fan J.
Chemosphere. 2019 Aug;229:618-630. doi: 10.1016/j.chemosphere.2019.04.099. Epub 2019 Apr 15.
PMID:
31102917
12.
Ştefănescu R, Stanciu GD, Luca A, Caba IC, Tamba BI, Mihai CT.
Molecules. 2019 Mar 24;24(6). pii: E1167. doi: 10.3390/molecules24061167. Review.
13.
Amedonu E, Brenker C, Barman S, Schreiber JA, Becker S, Peischard S, Strutz-Seebohm N, Strippel C, Dik A, Hartung HP, Budde T, Wiendl H, Strünker T, Wünsch B, Goebels N, Meuth SG, Seebohm G, Melzer N.
Front Neurol. 2019 Mar 1;10:178. doi: 10.3389/fneur.2019.00178. eCollection 2019.
14.
Matt L, Kim K, Chowdhury D, Hell JW.
Front Mol Neurosci. 2019 Jan 31;12:8. doi: 10.3389/fnmol.2019.00008. eCollection 2019. Review.
Many postsynaptic proteins undergo palmitoylation, the reversible attachment of the fatty acid palmitate to cysteine residues, which influences trafficking, localization, and protein interaction dynamics. Both palmitoylation by palmitoyl acyl transferases (PAT) and depalmitoylation by palmitoyl-protein thioesterases (PPT) is regulated in an activity-dependent, localized fashion. Recently, palmitoylation has received attention for its pivotal contribution to various forms of synaptic plasticity, the dynamic modulation of synaptic strength in response to neuronal activity. For instance, palmitoylation and depalmitoylation of the central postsynaptic scaffold protein postsynaptic density-95 (PSD-95) is important for synaptic plasticity. Here, we provide a comprehensive review of studies linking palmitoylation of postsynaptic proteins to synaptic plasticity.Free PMC Article
15.
Patel MV, Sewell E, Dickson S, Kim H, Meaney DF, Firestein BL.
J Neurotrauma. 2019 Jul 1;36(13):2129-2138. doi: 10.1089/neu.2018.6291. Epub 2019 Mar 28.
PMID:
30747034
16.
Zamzow DR, Elias V, Acosta VA, Escobedo E, Magnusson KR.
eNeuro. 2019 Feb 7;6(1). pii: ENEURO.0310-18.2019. doi: 10.1523/ENEURO.0310-18.2019. eCollection 2019 Jan-Feb.
Cognitive decline with aging is often due to altered levels of protein expression. The NMDA receptor (NMDAR) and the complex of proteins surrounding the receptor are susceptible to age-related changes in expression. In the frontal cortex of aged mice, there is a significant loss of expression of the GluN2B subunit of the NMDAR, an increase in Fyn expression, and no change in PSD-95. Studies have also found that, in the frontal cortex, phosphorylation of GluN2B subunits and palmitoylation of GluN2 subunits and NMDAR complex proteins are affected by age. In this study, we examined some of the factors that may lead to the differences in the palmitoylation levels of NMDAR complex proteins in the frontal cortex of aged animals. The Morris water maze was used to test spatial learning in 3- and 24-month-old mice. The acyl-biotinyl exchange method was used to precipitate palmitoylated proteins from the frontal cortices and hippocampi of the mice. Additionally, brain lysates from old and young mice were probed for the expression of fatty acid transporter proteins. An age-related increase of palmitoylated GluN2A, GluN2B, Fyn, PSD-95, and APT1 (acyl protein thioesterase 1) in the frontal cortex was associated with poorer reference memory and/or executive functions. These data suggest that there may be a perturbation in the palmitoylation cycle in the frontal cortex of aged mice that contributes to age-related cognitive declines.Free PMC Article
17.
Ben Mimouna S, Le Charpentier T, Lebon S, Van Steenwinckel J, Messaoudi I, Gressens P.
J Cell Physiol. 2019 Feb 4. doi: 10.1002/jcp.28245. [Epub ahead of print]
The present study examined the involvement of zinc (Zn)-transporters (ZnT3) in cadmium (Cd)-induced alterations of Zn homeostasis in rat hippocampal neurons. We treated primary rat hippocampal neurons for 24 or 48 hr with various concentrations of CdCl2 (0, 0.5, 5, 10, 25, or 50 μM) and/or ZnCl 2 (0, 10, 30, 50, 70, or 90 μM), using normal neuronal medium as control. By The CellTiter 96 ® Aqueous One Solution Cell Proliferation Assay (MTS; Promega, Madison, WI) assay and immunohistochemistry for cell death markers, 10 and 25 μM of Cd were found to be noncytotoxic doses, and both 30 and 90 μM of Zn as the best concentrations for cell proliferation. We tested these selected doses. Cd, at concentrations of 10 or 25 μM (and depending on the absence or presence of Zn), decreased the percentage of surviving cells. Cd-induced neuronal death was either apoptotic or necrotic depending on dose, as indicated by 7-AAD and/or annexin V labeling. At the molecular level, Cd exposure induced a decrease in hippocampal brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) and Erk1/2 signaling, a significant downregulation of the expression of learning- and memory-related receptors and synaptic proteins such as the NMDAR NR2A subunit and PSD-95, as well as the expression of the synapse-specific vesicular Zn transporter ZnT3 in cultured hippocampal neurons. Zn supplementation, especially at the 30 μM concentration, led to partial or total protection against Cd neurotoxicity both with respect to the number of apoptotic cells and the expression of several genes. Interestingly, after knockdown of ZnT3 by small interfering RNA transfection, we did not find the restoration of the expression of this gene following Zn supplementation at 30 μM concentration. These data indicate the involvement of ZnT3 in the mechanism of Cd-induced hippocampal neurotoxicity.
18.
Diaz A, Jeanneret V, Merino P, McCann P, Yepes M.
J Cell Sci. 2019 Feb 28;132(5). pii: jcs224196. doi: 10.1242/jcs.224196.
Neuronal depolarization induces the synaptic release of tissue-type plasminogen activator (tPA). Cyclin-dependent kinase-5 (Cdk5) is a member of the family of cyclin-dependent kinases that regulates cell migration and synaptic function in postmitotic neurons. Cdk5 is activated by its binding to p35 (also known as Cdk5r1), a membrane-anchored protein that is rapidly degraded by the proteasome. Here, we show that tPA prevents the degradation of p35 in the synapse by a plasminogen-dependent mechanism that requires open synaptic N-methyl-D-aspartate (NMDA) receptors. We show that tPA treatment increases the abundance of p35 and its binding to Cdk5 in the postsynaptic density (PSD). Furthermore, our data indicate that tPA-induced p35-mediated Cdk5 activation does not induce cell death, but instead prevents NMDA-induced ubiquitylation of postsynaptic density protein-95 (PSD-95; also known as Dlg4) and the removal of GluR1 (also known as Gria1)-containing α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors from the PSD. These results show that the interaction between tPA and synaptic NMDA receptors regulates the expression of AMPA receptor subunits in the PSD via p35-mediated Cdk5 activation. This is a novel role for tPA as a regulator of Cdk5 activation in cerebral cortical neurons.Free Article
19.
Linnoila J, Pulli B, Armangué T, Planagumà J, Narsimhan R, Schob S, Zeller MWG, Dalmau J, Chen J.
Neurol Neuroimmunol Neuroinflamm. 2018 Dec 26;6(2):e529. doi: 10.1212/NXI.0000000000000529. eCollection 2019 Mar.
20.
Montalban E, Al-Massadi O, Sancho-Balsells A, Brito V, de Pins B, Alberch J, Ginés S, Girault JA, Giralt A.
Transl Psychiatry. 2019 Jan 15;9(1):3. doi: 10.1038/s41398-018-0352-y.

Juomaveden fluoridi ja mikrogliavaikutus

https://www.ncbi.nlm.nih.gov/pubmed/30273629
Pohdittavaksi 

Kortikaaliset proteiiniverkot ja PDZ- domaanit. NMDA reseptori

https://www.cell.com/current-biology/fulltext/S0960-9822(96)00737-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0960982296007373%3Fshowall%3Dtrue

Dispatch| Volume 6, ISSUE 11, P1385-1388, November 01, 1996

Protein–protein interactions: PDZ domain networks


Open ArchiveDOI:https://doi.org/10.1016/S0960-9822(96)00737-3




Biochemical analyses using both in vivo and in vitro binding assays suggest that PDZ domains are modular protein-binding domains that have at least two distinct mechanisms for binding: they can bind to specific recognition sequences at the carboxyl termini of proteins, or they can dimerize with other PDZ domains. For example, the carboxyl termini of both the N-methyl D-aspartate (NMDA) receptor and the Shaker-type potassium channel have been identified as ligands for the first (PDZ 1) and second (PDZ 2) PDZ domains of three related proteins — the synapse-associated proteins PSD-95, chapsyn 110 and the human homolog of the Drosophila Dlg protein (hdlg) [
,
,
,
].

lördag 16 november 2019

Aivojen valkea aine ja atraktiinigeeni ATRN(20p13) , T2DM, obesitas ja monosyyttien DPPT-L.

https://link.springer.com/article/10.1007%2Fs10048-017-0515-7
2017 Abstract








Hypomyelinating leukodystrophies are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. We used whole exome analysis to study the molecular basis of hypomyelinating leukodystrophy in two sibs from a consanguineous family. A homozygous mutation, c.3068+5G>A, was identified in the ATRN gene, with the consequent insertion of an intronic sequence into the patients’ cDNA and a predicted premature termination of the ATRN polypeptide. ATRN encodes Attractin, which was previously shown to play a critical role in central myelination. Several spontaneous ATRN rodent mutants exhibited impaired myelination which was attributed to oxidative stress and accelerated apoptosis. ATRN can now be added to the growing list of genes associated with hypomyelinating leukodystrophy. The disease seems to be confined to the CNS; however, given the young age of our patients, longer follow-up may be required. Keywords

Attractin Hypomyelination Leukodystrophy 


Lisätietoa tästä geenistä PubMed Gene lähteestä:
 https://www.ncbi.nlm.nih.gov/gene/8455

Also known as MGCA; DPPT-L
Summary This gene encodes both membrane-bound and secreted protein isoforms. A membrane-bound isoform exhibits sequence similarity with the mouse mahogany protein, a receptor involved in controlling obesity. A secreted isoform is involved in the initial immune cell clustering during inflammatory responses that may regulate the chemotactic activity of chemokines. [provided by RefSeq, Apr 2016]
Expression Ubiquitous expression in duodenum (RPKM 20.8), thyroid (RPKM 17.2) and 25 other tissues
 (Kelch-domeenit voi laskea jaksoista ,joissa on GG----Y----W motiivi.
 
  1. NM_001207047.3NP_001193976.1  attractin isoform 4
    Status: REVIEWED
    Description
    Transcript Variant: This variant (4) uses an alternate splice junction at the 3' end of the first exon and differs in the 3' UTR and coding region compared to variant 1. The resulting isoform (4) has distinct N- and C-termini compared to isoform 1. Unlike isoform 1, which is membrane-bound, isoform 4 is secreted.
    Source sequence(s)
    AK293010, AK302730, AL132773, BC101705, DA368237
    UniProtKB/Swiss-Prot
    O75882
    UniProtKB/TrEMBL
    B4DZ36
    Conserved Domains (7) summary
    cd03597
    Location:672804
    (ALP)CLECT_attractin_like: C-type lectin-like domain (CTLD) of the type found in human and mouse attractin (AtrN) and attractin-like protein (ALP). CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. Mouse AtrN (the product of the mahogany gene) has been shown to bind Agouti protein and to function in agouti-induced pigmentation and obesity. Mutations in AtrN have also been shown to cause spongiform encephalopathy and hypomyelination in rats and hamsters. The cytoplasmic region of mouse ALP has been shown to binds to melanocortin receptor (MCR4). Signaling through MCR4 plays a role in appetite suppression. Attractin may have therapeutic potential in the treatment of obesity. Human attractin (hAtrN) has been shown to be expressed on activated T cells and released extracellularly. The circulating serum attractin induces the spreading of monocytes that become the focus of the clustering of non-proliferating T cells.
    cd00041
    Location:23131
    CUB; CUB domain; extracellular domain; present in proteins mostly known to be involved in development; not found in prokaryotes, plants and yeast.
    cd00055
    Location:946991
    EGF_Lam; Laminin-type epidermal growth factor-like domain; laminins are the major noncollagenous components of basement membranes that mediate cell adhesion, growth migration, and differentiation; the laminin-type epidermal growth factor-like module occurs in ...
    sd00038
    Location:385434
    Kelch; KELCH repeat [structural motif]
    pfam01437
    Location:816867
    PSI; Plexin repeat
    pfam13415
    Location:234284
    Kelch_3; Galactose oxidase, central domain
    pfam13854
    Location:274312
    Kelch_5; Kelch motif



    REFERENCE   3  (residues 1 to 1156)
      AUTHORS   Laudes M, Oberhauser F, Schulte DM, Schilbach K, Freude S,
                Bilkovski R, Schulz O, Faust M and Krone W.
      TITLE     Dipeptidyl-peptidase 4 and attractin expression is increased in
                circulating blood monocytes of obese human subjects
      JOURNAL   Exp. Clin. Endocrinol. Diabetes 118 (8), 473-477 (2010)
       PUBMED   20198559
      REMARK    GeneRIF: The levels of both dipeptidyl-peptidase 4 and attractin in
                circulating monocytes were significantly higher in obese subjects
                as compared with levels in lean controls or in subjects with type 2
                diabetes.
    Atraktiinivajeen merkitys. Tutkimuskoe-eläimeltä:)
    https://www.ncbi.nlm.nih.gov/pubmed/19931230 
    2010 Feb 2;1312:145-55. doi: 10.1016/j.brainres.2009.11.027. Epub 2009 Nov 18.
    Abnormal myelinogenesis both in the white and gray matter of the attractin-deficient mv rat.
    Laboratory of Veterinary Pathology, Osaka Prefecture University, Rinku Orai-Kita, Izumisano, Osaka 598-8531, Japan.

    Abstract

    The myelin vacuolation (mv) rat exhibits hypomyelination and vacuole formation in the myelin throughout the CNS, caused by a null mutation in the attractin gene. Myelin alterations in the spinal cord of mv rats progress during postnatal development and are more prominent in the white matter. In contrast, microglial activation is confined to the gray matter of mv rats. We here investigate the distribution and expression patterns of major CNS myelin proteins in the spinal cord of mv rats during the development of the myelin lesions. Immunohistochemical and Western blot analyses demonstrated a considerable reduction in the expression of major CNS myelin proteins both in the white and gray matter of mv rats, which was consistent with the morphological alterations of myelin sheaths. Real-time PCR analysis revealed a significant decrease in expression of proteolipid protein (PLP) mRNA both in the white and gray matter of mv rats. However, there was no significant difference between control and mv rats in the cell number of PLP mRNA-positive oligodendrocytes either in the white or gray matter, suggesting an impairment of myelin protein production by oligodendrocytes. Our results indicate that myelinogenesis but not oligodendrogenesis is severely altered both in the white and gray matter of mv rats.
    PMID:
    19931230
    DOI:
    10.1016/j.brainres.2009.11.027

måndag 11 november 2019

Myelinaatio ja Dyneiini

https://www.ncbi.nlm.nih.gov/pubmed/23167977
 
2012 Nov 20;7:37. doi: 10.1186/1749-8104-7-37. Schwann cell myelination requires Dynein function. Langworthy MM1, Appel B.
Department of Pediatrics, University of Colorado School of Medicine, MS 8108, Aurora, CO, 80045, USA. Abstract  BACKGROUND: Interaction of Schwann cells with axons triggers signal transduction that drives expression of Pou3f1 and Egr2 transcription factors, which in turn promote myelination. Signal transduction appears to be mediated, at least in part, by cyclic adenosine monophosphate (cAMP) because elevation of cAMP levels can stimulate myelination in the absence of axon contact. The mechanisms by which the myelinating signal is conveyed remain unclear. RESULTS: By analyzing mutations that disrupt myelination in zebrafish, we learned that Dynein cytoplasmic 1 heavy chain 1 (Dync1h1), which functions as a motor for intracellular molecular trafficking, is required for peripheral myelination. In dync1h1 mutants, Schwann cell progenitors migrated to peripheral nerves but then failed to express Pou3f1 and Egr2 or make myelin membrane. Genetic mosaic experiments revealed that robust Myelin Basic Protein expression required Dync1h1 function within both Schwann cells and axons. Finally, treatment of dync1h1 mutants with a drug to elevate cAMP levels stimulated myelin gene expression. CONCLUSION: Dync1h1 is required for retrograde transport in axons and mutations of Dync1h1 have been implicated in axon disease. Our data now provide evidence that Dync1h1 is also required for efficient myelination of peripheral axons by Schwann cells, perhaps by facilitating signal transduction necessary for myelination.
PMID:
23167977
PMCID:
PMC3520773
DOI:
10.1186/1749-8104-7-37
[Indexed for MEDLINE]
Free PMC Article