Neuroprotektiivinen E3 ubikitiiniligaasi MGRN1(RNF156) (16p13.3)

 RNF156, MGRN1 (16p13.3), Mahogunin Ring Finger-1
Expr. Spleen, brain.
https://www.ncbi.nlm.nih.gov/gene/?term=RNF156

Preferred Names

E3 ubiquitin-protein ligase MGRN1

Names

RING finger protein 156

RING-type E3 ubiquitin transferase MGRN1

mahogunin RING finger protein 1

mahogunin ring finger 1, E3 ubiquitin protein ligase

probable E3 ubiquitin-protein ligase MGRN1

Conserved Domains (3) summary

PHA02929
Location:232 → 331

PHA02929; N1R/p28-like protein; Provisional

• The poxviral RING protein p28 is a ubiquitin ligase that targets ubiquitin to viral replication factories.J. Virol. 2005 Jan ; 79(1):597-601
• Genome of deerpox virus.J. Virol. 2005 Jan ; 79(2):966-77
• Genome comparison of a nonpathogenic myxoma virus field strain with its ancestor, the virulent Lausanne strain.J. Virol. 2009 Mar ; 83(5):2397-403

TIGR00599
Location:273 → 449

rad18; DNA repair protein rad18.All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

pfam13920
Location:274 → 319

zf-C3HC4_3; Zinc finger, C3HC4 type (RING finger)

 

Related articles in PubMed

1. MGRN1-mediated ubiquitination of α-tubulin regulates microtubule dynamics and intracellular transport. Mukherjee R, et al. Traffic, 2017 Dec. PMID 28902452
2. Mahogunin ring finger-1 (MGRN1) suppresses chaperone-associated misfolded protein aggregation and toxicity. Chhangani D, et al. Sci Rep, 2013. PMID 23756845, Free PMC Article
3. Calmodulin regulates MGRN1-GP78 interaction mediated ubiquitin proteasomal degradation system. Mukherjee R, et al. FASEB J, 2019 Feb. PMID 30230921
4. Aging Triggers Cytoplasmic Depletion and Nuclear Translocation of the E3 Ligase Mahogunin: A Function for Ubiquitin in Neuronal Survival. Benvegnù S, et al. Mol Cell, 2017 May 4. PMID 28475871A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1. Once in the nucleus, MGRN1 potentiates the transcriptional cellular response to proteotoxic stress. Inhibition of MGRN1 impairs ATF3-mediated neuronal responsiveness to proteosomal stress and increases neuronal stress, while increasing MGRN1 ameliorates signs of neuronal aging, including cognitive performance in old animals. Our results imply that, among others, the strength of neuronal survival in a proteasomal deterioration background, like during aging, depends on the fine-tuning of ubiquitination-deubiquitination.
5. DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA. Tang Q, et al. Oncotarget, 2016 Sep 27. PMID 27577081, Free PMC Article

1. depletion of MGRN1 activity may hamper physiologically important processes like mitochondrial movement in neuronal processes and intracellular transport of ligands through the endosomal pathway thereby contributing to the pathogenesis of neurodegeneration in certain types of prion diseases
2. In a heterologous expression system, MC1R-dependent Arrestins B ubiquitination was enhanced by overexpression of MGRN1 and was impaired by siRNA-mediated MGRN1 knockdown thus pointing to MGRN1 as the responsible E3-ligase.
3. Hypomethylation of CpG sites in RPTOR, MGRN1 and RAPSN in blood is associated with breast cancer.
4. Regulation of Mfn1 by MGRN1 and the proteasome modulates mitochondrial fusion.
5. Catalytic inactivation of MGRN1 results in elevated levels of GP78 and a consequential increase in the initiation of mitophagy.
6. Mahogunin-mediated alpha-tubulin ubiquitination via noncanonical K6 linkage regulates microtubule stability and mitotic spindle orientation.
7. data suggest that MGRN1 selectively targets misfolded proteins for degradation and may exhibit viable therapeutic potential for the treatment of spongiform neurodegeneration
8. It therefore seems probable that the role of MGRN1 in the adrenal relates to the trafficking and/or degradation of the melanocortin 2 receptor.
9. Clinical trial of gene-disease association and gene-environment interaction. (HuGE Navigator)D

Select item 310898071.

Chronic and age-dependent effects of the spongiform neurodegeneration-associated MGRN1 E3 ubiquitin ligase (RFN156), Mahoquin Ring finger, Chr.11)    on mitochondrial homeostasis.

Gunn TM, Silvius D, Lester A, Gibbs B.

Mamm Genome. 2019 May 14. doi: 10.1007/s00335-019-09802-7. [Epub ahead of print]

Spongiform encephalopathy is an intriguing yet poorly understood neuropathology characterized by vacuoles, demyelination, and gliosis.
 It is observed

• in patients with prion disease, 
• primary mitochondrial disease,
•  HIV-1 infection of the brain, and 
• some inherited disorders,

 but the underlying mechanism of disease remains unclear. The brains of mice lacking the MGRN1 E3 ubiquitin ligase develop vacuoles by 9 months of age. MGRN1-dependent ubiquitination has been reported to regulate mitofusin 1 and GP78, suggesting MGRN1 may have a direct effect on mitochondrial homeostasis. Here, we demonstrate that some MGRN1 localizes to mitochondria, most likely due to N-myristoylation, and mitochondria in cells from Mgrn1 null mutant mice display fragmentation and depolarization without recruitment of the parkin E3 ubiquitin ligase. The late onset of pathology in the brains of Mgrn1 null mutant mice suggests that a further, age-dependent effect on mitochondrial homeostasis may be required to trigger vacuolation. Parkin protein and mRNA levels showed a significant decline in the brains of Mgrn1 null mutant mice by 12 months of age. To test whether loss of parkin triggers vacuolation through a synergistic effect, we generated Mgrn1; parkin double mutant mice. By 1 month of age, their brains demonstrated more severe mitochondrial dysfunction than Mgrn1 null mutants, but there was no effect on the age-of-onset of spongiform neurodegeneration. Expression of the ATF4 transcription factor, a key regulator of the mitochondrial stress response, also declined in the brains of aged Mgrn1 null mutant mice. Together, the data presented here indicate that loss of MGRN1 has early, direct effects on mitochondrial homeostasis and late, indirect effects on the ability of cells to respond to mitochondrial stress.DOI:10.1007/s00335-019-09802-7

Glioomatutkimuksesta väitöskirja 2019

https://biomedicine.gu.se/biomedicine/News_and_Events/event-detail/?eventId=70136894648

Susanna Larsson - Cell-based models for studying paediatric high grade gliomas

Dissertation

Thesis defense at the Sahlgrenska Academy, Institute of Biomedicine, dept of laboratory medicine

Opponent:
Silvia Marino, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Assessment committee:
Khalil Helou, dept. of oncology, inst. of clinical sciences
Elin Esbjörner Winters, dept. of Biology and Biological Engineering, Chemical Biology, Chalmers University of Technology

In this tttttttttttttt, three pre-clinical models were established which can be used to generate new knowledge and explore new treatment options for paediatric brain tumours. 

 Lapsuusiän  syöpää esiintyy 16:100 000 alle 15-vuotiaissa.
Alle 10-vuotiailla näistä on leukemioita 10% Akuutin lymfaattisen leukemian suhteen on kuitenkin nykyään 5- vuoden elossapysymisprosentti jomiltei 90%.
Keskushermostotuumoreita on 28%.
I
Neuroepiteliaalisesta kudoksesta lähteviä glioomia,
 astrosytoomia on  aivomaligniteeteista noin 45% ( niistä  matala-asteisesti maligneja  I-II noin 31% ja korkea-asteisesti maligneja III-IV asteisia  noin 6%).
Ependymoomia ( aivokammiosta alkuisin olevia) 10.5%,
Oligodendroglioomia 2,5 % ja ne alkavat oligodendrosyyteistä,
Aivorungon glioomia 2,6%.
II
Enbryonaalisia tuumoreita 18.8%
Näissä on medullobastoomia, pikkuaivosolusita lähteviä, 14.8%
ATRT  p,3 % ( atyyppiset teratoidit/rhabdoidit tuumorit)
PNET  (prim. neuroektodermaaliset tuumorit) on siirretty WHO-listalta toiseen ryhmään.
Pediatrista  GBM 2,3%
HGG (High-grade  glioma): anaplastista astrosytoomaa, diffuusia infiltroivaa pontista gliomaa.

Nämä jaetaan 6 ryhmään perustaen DNA-metylaatiotietoihin, ikään, jolloin tuumori alkoi,  tuumorin paikallistumiseen, geeni-ilmenntymiseen, onkogeenivaikuttajiin ja elossapysymisaikaan.
K27
G34
IDH, isositraattidehydrogenaasi
RTK1
Mesenkymaalinen
PXA, pleomorfinen xantoastrosytooma

Aivotuumorit ovat lapsilla suurin ryhmä solideja tuumoreita ja niiden tiliin  lasketaan  useimmat syövästä johtuvat kuolemantapaukset. Astrosytoomia on suurin ryhmä aivotuumoreista  ja korkean asteen gliooma HGG taas on niistä vaarallisin eikä siihen ole tehokkaita hoitoja.  Sen takia tämän taudin parempi käsittäminen on tarpeen ja uusia terapeuttisia  optioita tarvitaan kiireellisesti.
I. Tutkimuksien edistämiseksi  ensimmäisessä osatyössä valmistettiin  viljeltyjä gliooma kantasoluja(GCS), joilla   säilyi proliferoimiskyky ja joissa  esiintyi  hermonkantasolujen markkerit, ja ne antoivat vastetta  differentoiviin signaalilinjoihin.  Lisäksi koehiiriin istutettuina ne panivat alkuun tuumorinkasvun.
II. Toisessa osatyössä seurattiin GSC-transplantaatin aiheuttaman  tuumorin kasvua koehiirissä, xenograftituumoreiden  bistologisia ja molekulaarisia piirteitä. Eloonjääminen  hiirien tuumorista korreloi ihmisten eloonjäämiseen  Lisäksi xenograftituumoreilla  oli sama kasvumalli kuin potilaiden tuumoreilla, geneettiset ja epigeneettiset muuntumiset olivat samanlaisia kuin alkuperäistuumorilla  ja GSC-linjalla.
III. Kolmannessa työssä oli eläinmallina seeprakala, jolla  tätä  gliooma (HGG) laatua tutkittiin, tuumorin alkamispotentiaalia ja invasoivia ominaisuuksia. Kalakudos otti transplantoidut glioomasolut hyvin vastaan ja solut invasoituivat  ympäröivään aivokudokseen jo parissa päivässä.
Täten tässä väitöstyössä tehtiin kolme prekliinistä mallia, joita voidaan käyttää uuden tiedon esiinsaamiseen  lapsuuden aivotuumoreista  ja uusien hoito-optioiden  löytämiseen.
 ..
Kirjassa on runsas luettelo käytetyistä termeistä, niiden lyhennyksistä.(Kirjoitin Abbreviations  itselleni muistiin vihkoon. Niissä on tgerminologiaa , joihin  perehdyn siten ajan myötä)
Tänään luin  CHROMO-domeenin  omaavista proteiineista, jotka mainittiin kirjassa. Kirjoitin niistä geenit (9) Solusykli-blogiini. Kirjassa kerroti taustaosassa histonimodifikaatiosta.


Väitös on edessäpäin, toukokuun lopulla.
Muistiin 16-5- 2019

Aivojen biomarkkereista uusi väitöstyö tänään. Fokus: iskeminen aivohalvaus

https://gupea.ub.gu.se/handle/2077/59055
osatyöt ovat:
I. Pedersen A, Redfors P, Lundberg L, Gils A, Declerck PJ, Nilsson S, Jood K, Jern C. Haemostatic biomarkers are associated with long-term recurrent vascular events after ischaemic stroke. Thromb Haemost. 2016;116: 537-543.
VISA ARTIKEL

II. Pedersen A, Stanne TM, Redfors P, Viken J, Samuelsson H, Nilsson S, Jood K, Jern C. Fibrinogen concentrations predict long-term cognitive outcome in young ischemic stroke patients. Res Pract Thromb Haemost. 2018;2:339-346.
VISA ARTIKEL

III. Pedersen A, Stanne TM, Nilsson S, Klasson S, Rosengren L, Holmegaard L, Jood K, Blennow K, Zetterberg H, Jern C. Circulating neurofilament light in ischemic stroke: Temporal profile and outcome prediction. Submitted manuscript.

IV. Söderholm M*, Pedersen A*, Lorentzen E, Stanne TM, Bevan S, Olsson M, Cole JW, Fernandez-Cadenas I, Hankey GJ, Jimenez-Conde J, Jood K, Lee J-M, Lemmens R, Levi C, Mitchell BD, Norrving B, Rannikmäe K, Rost NS, Rosand J, Rothwell PM, Scott R, Strbian D, Sturm JW, Sudlow C, Traylor M, Thijs V, Tatlisumak T, Woo D, Worrall BB, Maguire JM**, Lindgren A**, Jern C**, on behalf of the International Stroke Genetics Consortium, the NINDS-SiGN Consortium, and the Genetics of Ischaemic Stroke Functional Outcome (GISCOME) network. Genome-wide association meta-analysis of functional outcome after ischemic stroke. Neurology, 2019;92:e1271-e1283. *These authors contributed equally to this work. **These authors jointly supervised this work.
VISA ARTIKEL
The overall aim of this thesis was to identify novel biomarkers for ischemic stroke outcomes. The specific aims were to test the hypotheses that circulating concentrations of hemostatic biomarkers predict the long-term post-stroke risk of recurrent vascular events/death (paper I) and/or cognitive impairment (paper II) and that circulating concentrations of a marker of neuronal damage (neurofilament light chain, NfL) predict post-stroke functional and neurological outcomes (paper III) as well as to identify genetic variants associated with post-stroke functional outcome through a genome wide association study (GWAS) approach (paper IV). Papers I-III are based on the first 600 cases and 600 controls recruited to the Sahlgrenska Academy Study on Ischemic Stroke, which includes consecutive ischemic stroke cases aged 18-69 years and sex- and age-matched population-based controls. In cases, blood sampling was performed in the acute phase, after three months, and in a subset also 7 years post-stroke. Controls were sampled once. These blood samples were used to analyze the protein and genetic biomarkers investigated in this thesis. Vascular events and death up to 14 years after inclusion were identified. In cases, functional and neurological outcomes were assessed at 3 months by the modified Rankin scale (mRS) and the NIH Stroke Scale (NIHSS), respectively. At 2 years, the mRS was assessed again, and in a subsample, long-term (7-year) outcomes were assessed by mRS and NIHSS. The 7-year follow-up also included cognitive testing with the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS) and Trailmaking Test. Paper IV was based on a GWAS approach, i.e. genetic variations spread throughout the entire genome were analyzed with respect to their association to 3-month post-stroke functional outcome in a hypothesis free manner. This study was performed within the Genetics of Ischemic Stroke Functional Outcome (GISCOME) network, and included 6,165 ischemic stroke cases from 12 studies in Europe, USA and Australia. 
 In paper I, we found that plasma levels of hemostatic protein biomarkers were associated with vascular death and coronary events, but not with recurrent stroke.
 In paper II, we found that, in cases <50 at="" b="" index="" stroke="" years="">higher concentrations of the hemostatic protein fibrinogen were independently associated with worse cognitive outcome. 
 In paper III, we found that acute phase and 3-month serum levels of NfL were independently associated to NIHSS and mRS both in short- and long-term follow-up.
 In paper IV, we identified one genetic variant associated with functional outcome (mRS score 0-2 vs 3-6) at genome-wide significance. 
In addition, several genetic variants demonstrated suggestive associations, and some of these are located within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery.
 In conclusion, the results from this thesis demonstrate associations between circulating protein levels as well as genetic markers and ischemic stroke outcomes. These results add knowledge on potential mechanisms influencing outcomes after ischemic stroke and may in the long run contribute to a more personalized post-stroke management.

Kommentti: siis rheologisiä  tekijöitä 8gibrinogeenifunktio)  ja regeneraatiopotentiaalia  (sytoportektiivisuuden ylläpito) voidaan tarvitaessa  yksilöllisesti moduloida) . (Nrf2) 

Muita aivovamman biomarkkereita erikseen ja paneleina

. Duodecim 7/2019 kirjoittaa aiheesta
"Parempaa aivovammapotilaiden diagnostiikkaa ja hoitoa  verikokeen avulla?"
Siteeraan artikkelin  taustatekstiä:
(Jatkuu..)
 Edellä mainittujen proteiinibiomarkkereiden  (S100B, GFAP, UCH-L1) ohella  on tutkittu pieniä verestä mitattavia aineenvaihduntatuotteita kuten rasvahappoja ja glukoosijohdoksia aivovammadiagnostiikassa.    Toisin kuin usean proteiinin näiden aineenvaihduntabiomarkkereiden pääsy verenkiertoon  ei vaadi veri-aivoesteen vauriota.

Aivovammamarkkereiden tutkimuksessa metabolomiikan menetelmiä on toistaiseksi käytetty vileä vähän.
Hiljattain kuuden aineenvaihduntatuotteen yhdistelmän osoitettiin olevan suomalais-brittiläisessä kahden keskuksen tutkimuksessa jopa GFAP_UCH-L1- testiä tarkempi tunnistamaan TT-kuvantamista tarvitsevat potilaat.
Dickens AM, Posti JP, Takala RSK et al. Serum metabolites with computed tomography findings after traumatic brain injury. J neurotrauma 2018

Löydänkin paljon lähteitä hakemalla ylläolevalla tekstillä.  Tässä abstraktissa kerrotaan 8 eri biomarkkerin  tutkimuksesta akuutissa aivovammassa tarkoituksena  pystyä erottamaan  aivovamman eri vaikeusasteissa (Glascow Coma Scale)   TT- positiiviset ja TT negatiiviset aivovammat. 
Tutkimuksessa käytetyt proteiinibiomarkerit ovat:

• beta-amyloidiiisoformi 1-40(Abeta40) 
• beta-amyloidi-isoformi 1-42(Abeta42),
• gliaalinen fibrillaarinen asidinen proteiini GFAP,
• sydänrasvahappoa sitova proteiini H-FABP
• Interleukiini-10 (IL-10)
• kevyt neurofilamentti NF-L
• S100 kalsiumia sitova proteiini B (S100B) 
• Tau proteiini

 TT-negatiiviset ja TT-positiiviset potilaat erotti parhaiten biomarkkerit NF_L, GFAP ja tau  sekä lievien aivovammojen ryhmässä että kaikenasteisten aivovammojen ryhmissä.
Paras kolmen  panelikombinaatio kaikenasteisten aivovammojen ryhmissä oli GFAP +H-FABP + IL10 ja paras kolmen paneli  lievien vammojen ryhmässä oli H-FABP + S100B + tau.   Panelit koostuivat lähinnä eri biomarkkereista kuin niistä, jotka yksinään olivat parhaita erottamassa TT+ ja TT- potilaat.
https://www.liebertpub.com/doi/10.1089/neu.2018.6254 

Abstract

The aim of the study was to examine the ability of eight protein biomarkers and their combinations in discriminating computed tomography (CT)-negative and CT-positive patients with traumatic brain injury (TBI), utilizing highly sensitive immunoassays in a well-characterized cohort. Blood samples were obtained from 160 patients with acute TBI within 24 h of admission. Levels of β-amyloid isoforms 1–40 (Aβ40) and 1–42 (Aβ42), glial fibrillary acidic protein (GFAP), heart fatty-acid binding protein (H-FABP), interleukin 10 (IL-10), neurofilament light (NF-L), S100 calcium-binding protein B (S100B), and tau were measured.
Patients were divided into CT-negative (n = 65) and CT-positive (n = 95), and analyses were conducted separately for TBIs of all severities (Glasgow Coma Scale [GCS] score 3–15) and
 mild TBIs (mTBIs; GCS 13–15).
 NF-L, GFAP, and tau were the best in discriminating CT-negative and CT-positive patients, both in patients with mTBI and with all severities.
 In patients with all severities, area under the curve of the receiver operating characteristic (AUC) was 0.822, 0.817, and 0.781 for GFAP, NF-L, and tau, respectively.
 In patients with mTBI, AUC was 0.720, 0.689, and 0.676, for GFAP, tau, and NF-L, respectively. The best panel of three biomarkers for discriminating CT-negative and CT-positive patients in the group of all severities was a combination of GFAP+H-FABP+IL-10, with a sensitivity of 100% and specificity of 38.5%.
In patients with mTBI, the best panel of three biomarkers was H-FABP+S100B+tau, with a sensitivity of 100% and specificity of 46.4%. Panels of biomarkers outperform individual biomarkers in separating CT-negative and CT-positive patients. Panels consisted mainly of different biomarkers than those that performed best as an individual biomarker.

GFAP-UCH-L1-testistä biomarkkeri akuutissa aivovammassa

. Duodecim 7/2019 kirjoittaa aiheesta
"Parempaa aivovammapotilaiden diagnostiikkaa ja hoitoa  verikokeen avulla?"
Siteeraan artikkelin  taustatekstiä:

"Verestä mitattavat aivovammamerkkiaineet ( biomarkkerit) tekevät tuloaan arkipäivän lääketieteeseen.  Yhdysvaltain lääkevalvontaviranopmainen(FDA) hyväksyi vuonna 2018 ensimmäisen testin aivovammapotilaiden kuvantamistarpeen seulontaan. Vuosikymmenien tutkimuksen  ja  odotuksen jälkeen biomarkkerit tuovat lähivuosina aivovammojen arviointiin toivottua objektiivisuutta".

"Väestötason vuosittainen aivovammojen ilmaantuvuus on jopa 790/ 100 000. Näistä vammoista valtaosa on lieviä. Lievien aivovammojen toipumisennuste on pääosin hyvä. Lievää vaikeampiin aivovammoihin liittyy puolestaan merkittävää invaliditeettia ja kuolleisuutta."

"Akuutin aivovamman arvioinnin haasteet voidaan jakaa karkeasti kolmeen teemaan:
(1) pään päivystyksellisen (akuutin)  tietokonekerroskuvauksen (TT, tietokonetomografia) tarve,
(2) lievien aivovammojen diagnostisten kriteerien subjektiivisuus
ja
(3) toipumisennusteen määrittäminen.
Näihin haasteisiin on pyritty löytämään ratkaisuja  tavallisesta verikokeesta, perifeerisestä verestä proteomiikan, genomiikan, metabolomiikan ja immunologian keinoin löydetyillä biomarkkereilla tai biomarkkeriyhdistelmillä. "

"Pään TT-kuvaus on muodostunut kultaiseksi standardiksi kallonsisäisten vammojen akuuttitutkimuksena. (Golden standard:  acute computer tomography)".

Kuvantamistarvetta vähentäville biomarkkereille on selkeä tarve, sillä valtaosa tapaturman vuoksi tehtävistä pään TT-kuvauksista (  jotka ovat kalliitat ja altistavat jonisoivalle säteilylle) on löydöksettömiä, siis aivan normaalilöytöjä.
 ( Tässä tarkoituksessa  2013  on otettu jo käyttöön S100B, muta se ei ole  yksiselitteinen ja riittävä).

Viime vuonna (2018) FDA:n hyväksynnän saanut testi sisältää gliasoluperäisen glial fibrillary acidic (GFAP) ja neuroniperäisen ubiquitin carboxy terminal hydrolase L1 (UCH-L1)-proteiinin pitoisuusmäärityksen.
Nämä biomarkkerit ovat varsin aivokudosspesifisiä:  kuvantaen todettaville aivokudoksen akuuteille vaurioille  ne ovat herkkiä eivätkä  puolestaan reagoi  S100B:n tavoin herkästi kallon ulkopuolisiin vammoihin. Testi validoitiin laajassa tutkimuksessa, joka osoitti testin ennustavan luotettavasti TT(+)-aivovammalöydöksiä lievän aivovamman saaneilla potilailla.
Mikä hidastaa testin kliinistä käyttöönottoa?
Puuttuu riittävän nopeaa laboratorioanalytiikkaa ja hoitopaikkamittauslaitteita ( point-of-care-test) sekä viitearvot:  tarkat potilasryhmäkohtaiset  (esimerkiksi monivamma-, lapsi-,vanhus- ja kroonisia aivosairauksia sairastavat potilaat)  viitearvot uupuvat".  katson mitä tästä testistä löytyy tietoa (Huomaan että UCH-L1 onkin tuttu  molekyyli, se on  deubikitinaasien DUB  yhdeestä alaryhmästä UCH, joten otan siitä erikseen  seuraavassa  geenitiedot ja löytöhistorian, nimet ja referenssit  talteen myös vihkooni DUB-luetteloon). Muitakin biomarkkereita  mainitaan  Duodecimin artikkelisas ja jatkan niistä erikseen.

Search results

Items: 5

Select item 300541511.

GFAP-UCH-L1 test

Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study.

Bazarian JJ, Biberthaler P et al. 

Similar articles:

Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study.

Bazarian JJ, Biberthaler P et al. 

Similar articles

Löytyi suomalainen tutkimus. 

 

Select item 269633302.

The Levels of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 During the First Week After a Traumatic Brain Injury: Correlations With Clinical and Imaging Findings.

Posti JP, Takala RS, Runtti H, Newcombe VF, Outtrim J, Katila AJ, Frantzén J, Ala-Seppälä H, Coles JP, Hossain MI, Kyllönen A, Maanpää HR, Tallus J, Hutchinson PJ, van Gils M, Menon DK, Tenovuo O.

Neurosurgery. 2016 Sep;79(3):456-64. doi: 10.1227/NEU.0000000000001226. Abstract BACKGROUND:

Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) are promising biomarkers of traumatic brain injury (TBI).
OBJECTIVE:
We investigated the relation of the GFAP and UCH-L1 levels to the severity of TBI during the first week after injury.
METHODS:
Plasma UCH-L1 and GFAP were measured from 324 consecutive patients with acute TBI and 81 control subject enrolled in a 2-center prospective study. The baseline measures included initial Glasgow Coma Scale (GCS), head computed tomographic (CT) scan at admission, and blood samples for protein biomarkers that were collected at admission and on days 1, 2, 3, and 7 after injury.
RESULTS:
Plasma levels of GFAP and UCH-L1 during the first 2 days after the injury strongly correlated with the initial severity of TBI as assessed with GCS. Additionally, levels of UCH-L1 on the seventh day after the injury were significantly related to the admission GCS scores. At admission, both biomarkers were capable of distinguishing mass lesions from diffuse injuries in CT, and the area under the curve of the receiver-operating characteristic curve for prediction of any pathological finding in CT was 0.739 (95% confidence interval, 0.636-0.815) and 0.621 (95% confidence interval, 0.517-0.713) for GFAP and UCH-L1, respectively.
CONCLUSION:
These results support the prior findings of the potential role of GFAP and UCH-L1 in acute-phase diagnostics of TBI. The novel finding is that levels of GFAP and UCH-L1 correlated with the initial severity of TBI during the first 2 days after the injury, thus enabling a window for TBI diagnostics with latency.
ABBREVIATIONS:
AUC, area under the curve
CI, confidence interval
ED, emergency department
GCS, Glasgow Coma Scale
GFAP, glial fibrillary acidic protein
IMPACT, International Mission for Prognosis and Clinical Trial
ROC, receiver-operating characteristic
TBI, traumatic brain injury
TRACK-TBI, Transforming Research and Clinical Knowledge in Traumatic Brain Injury
UCH-L1, ubiquitin C-terminal hydrolase-L1.

Similar articles

UCH-L1 , PARK5 (4p13)

Tausta tieto:
 Mihin ryhmään ubikitiiniin vaikuttava entsyymi UCHL1 kuuluu?: 

Tämän UCHL1 geenin (4p13)  koodaman proteiinin ryhmäkuuluvuus on
 DUB, deubikitinaasit  
Deubikitinaaseja on satakunta ja niillä on 5 alaperhettä. Niisä on paljon  vaikutus resursseja tulevaisiin aikoihin asti, kun niitä saa kartoitetuksu. UCHL1  heräsi eloon uudestaan  viime vuosina ja kuten 2018 aikaan  siitä on tullut paljon tuoretta tietoa, jota voi hyödyntöä koska  sen expressio on vahvasti neuronaalinen, aivo. 

DUB- Alaperheet ovat:
USP (57 kpl),Ubiquitin Specific  proteases

UCH (4 kpl) , Ubiquitin C-terminal Hydrolases
OTUS (14) , Ovarian Tumor proteases
MJD (4) , Machado-Joseph-Disease protease, SCA3
JAMM (11), Jab1/Pad1/MPN-domain containig metalloenzymes 


UCH-joukko on  seuraava:
BAP1
UCH-L1
UCH-L3
UCH-L5 (UCH37; CGI-70)
Siis nyt katson UCH-L1  deubikitinaasista enemmän tietoa:

UCH-L1(4p13)

https://www.ncbi.nlm.nih.gov/pubmed/30788389
 https://www.ncbi.nlm.nih.gov/gene/7345

Also known as

NDGOA; PARK5; PGP95; SPG79; PGP9.5; Uch-L1; HEL-117; PGP 9.5; HEL-S-53

Summary

The protein encoded by this gene belongs to the peptidase C12 family. This enzyme is a thiol protease that hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. This gene is specifically expressed in the neurons and in cells of the diffuse neuroendocrine system. Mutations in this gene may be associated with Parkinson disease.[provided by RefSeq, Sep 2009]

Expression

Biased expression in brain (RPKM 389.7), adrenal (RPKM 70.8) and 2 other tissues See more Orthologs mouse all

Preferred Names

ubiquitin carboxyl-terminal hydrolase isozyme L1

Names

epididymis luminal protein 117

epididymis secretory protein Li 53

neuron cytoplasmic protein 9.5

ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)

ubiquitin thioesterase L1

ubiquitin thiolesterase

NP_004172.2

• EC 3.4.19.12

Related articles in PubMed

1. The deubiquitinating enzyme UCHL1 is a favorable prognostic marker in neuroblastoma as it promotes neuronal differentiation. Gu Y, et al. J Exp Clin Cancer Res, 2018 Oct 25. PMID 30359286, Free PMC Article
2. UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch. Kupczyk P, et al. Biomed Res Int, 2018. PMID 30148172, Free PMC Article
3. Upregulation of Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Mediates the Reversal Effect of Verapamil on Chemo-Resistance to Adriamycin of Hepatocellular Carcinoma. Yang G, et al. Med Sci Monit, 2018 Apr 8. PMID 29627846, Free PMC Article
4. High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients. Nakao K, et al. Int J Gynecol Cancer, 2018 May. PMID 29489474
5. Ubiquitin C-Terminal Hydrolase L1 regulates autophagy by inhibiting autophagosome formation through its deubiquitinating enzyme activity. Yan C, et al. Biochem Biophys Res Commun, 2018 Mar 4. PMID 29462615

See all (275) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. high expression is a strong marker of poor prognosis of endometrial cancer
2. these results identified UCHL1 as a target podocyte protein of autoantibodies in a set of relapsing patients and support a causative role of anti-UCHL1 autoantibodies in the development of idiopathic steroid sensitive nephrotic syndrome
3. serum level not significantly elevated in newborns at risk for hypoxic ischemic encephalopathy but with normal EEGs
4. observed significantly altered density of PGP 9.5-positive axonal nerve terminals in pruritic lesional and nonlesional psoriatic skin compared with controls;PGP 9.5 expression by suprabasal keratinocytes (SBKs) was significantly increased in itchy skin lesions compared to skin without itch.
5. This study demonstrated that UCHL1 expression is induced by HCV infection. UCHL1 stimulates JNK phosphorylation and signaling related to HSCs activation after binding to the cell surface of HSCs.
6. Study showed that UCHL1 could serve as a prognostic marker indicating a favorable clinical outcome in Neuroblastoma (NB). UCHL1 expression was higher in ganglioneuroblastomas/ganglioneuromas (GNB/ GN) and well-differentiated NB than poorly differentiated NB, and UCHL1 expression was strongly associated with differentiation markers, indicating the positive correlation between UCHL1 expression and NB differentiation.
7. The proteins UCH-L1 and alpha-internexin could be independent prognostic biomarkers of pancreatic neuroendocrine tumors.
8. We have also demonstrated that UCHL1 S-nitrosylation provides seeding for faster aggregation of a-synuclein. Finally, the in vitro nitrosylation of UCHL1 was corroborated with rotenone induced mouse model of PD
9. In newborns undergoing cardiac surgery, ubiquitin C-terminal hydrolase 1 showed a significant rise at 0 hours in the deep hypothermic circulatory arrest group compared to baseline. Levels returned to baseline at 12 hours. There was an early rise in UCHL1 at 0 hours in the cardiopulmonary bypass group.
10. Overexpression of UCHL1 genes promoted apoptosis in cells treated with VER+ADM. UCHL1 knockdown using siRNA weakened the effect of ADM+VER, indicating that ADM+VER promotes HCC cell apoptosis and that UCHL1 genes participate in VER-mediated promotion in tumor cell apoptosis.

. Structure: History

https://www.ncbi.nlm.nih.gov/protein/NP_004172.2

Maailmassa etsitään biomarkkereita aivotraumojen diagnostisiin ja monitoriointitarpeisiin .

S100-proteiiniperheen S100B on eräs biomarkkeri, mutta se ei ole  spesifinen keskushermoston  sisäisille vaurioille. Duodecim 7/2019 kirjoittaa aiheesta
"Parempaa aivovammapotilaiden diagnostiikkaa ja hoitoa  verikokeen avulla?"
Vuonna 2013 skandinaavinen neurotraumakomitea julkaisi ensimmäisen aivovammojen hoitosuosituksen, joka integroi aivovammapotilaan kliiniseen arviointiin  biomarkkerin. kyseinen suositus sisältää hermotukisoluissa ( glia)  ekspressoituvan S100B-proteiinin määrityksen osana pienen riskin lievän aivovamman saaneen potilaan kuvantamistarpeen arviointia". Kyseisen suosituksen on raportoitu vähentävän sekä diagnostiikkakustannuksia, että pään tietokonetomografioiden määrää".  (Niistä suurin osa on ilman löydöstä ja  antaa jonisoivaa säteilyä joka kertyessään  nostaa syöpäriskiä, joten turhia kuvauksia tulisi välttää ja kuvaustarve tulisi  varmistaa  verikokeista  lievissä  aivovammoissa - ei edes  lumbaalipunktiosta, joka on invasiivinen diagnostinen menetelmä. Lieviä  aivovammoja tulee  lisääntyvässä määrin  jo urheilun alueelta, esim jääkiekkoilusta).
 " Mainitun  biomarkkerin S100B   käyttöä rajoittaa kuitenkin keskushermoston ulkopuolinen ekspressio, jonka vuosi merkkiaine reagoi muun muassa tuki- ja liikuntaelimistön vammoihin. S100B ei sovellu itsenäiseksi testiksi aivovammoihin, vaan sitä on käytettävä yhdessä kliinsiten löydösten kansas, kuten on todettu skandinaavisessa suosituksessa.  toistaiseksi tämän hoitosuosituksen luotettavuudesta on vielä vähän tutkimusnäyttöä".
.

Ensinnäkin vähän  S100-proteiiniperheestä Pub med haku  "S100 functions"(2013).
https://www.ncbi.nlm.nih.gov/pubmed/22834835

Curr Mol Med. 2013 Jan;13(1):24-57. tämä on laaja artikkeli kaiksita S100 proteiineista ja otan siitä sitaatin vain tästä S100B:   (Jatkan toiseen otsikkoon   Duodecimin mainitsemista muista uusista biomarkkereista).

Functions of S100 proteins.

Donato R¹, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, Geczy CL. Abstract

The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.

Free PMC Article

Fig. (6)

Schematic representation of proposed intracellular effects of S100B. S100B interacts with several intracellular proteins as shown thereby regulating protein phosphorylation, enzyme activities, the state of assembly of certain cytoskeleton components, the transcription factor p53, protein degradation, cell proliferation, locomotion and differentiation, dark adaptation of photoreceptors, Ca²⁺ homeostasis and the innate inflammatory response.

S100B

S100B is expressed in astrocytes, certain neuronal populations, Schwann cells, melanocytes, chondrocytes, adipocytes, skeletal myofibers and associated satellite cells, certain dendritic cell and lymphocyte populations and a few other cell types [7]. It acts as a stimulator of cell proliferation and migration and an inhibitor of apoptosis and differentiation [101-111] (Fig. 6), which might have important implications during brain, cartilage and skeletal muscle development and regeneration/repair, activation of astrocytes in the course of brain damage and neurodegenerative processes, and of cardiomyocyte remodeling after infarction, as well as in melanomagenesis and gliomagenesis. In particular, downregulation of S100B expression in precursor cells in a defined temporal window appears to be permissive for cell differentiation [101-106,108-110]. Sex-determining region Y-type high mobility group box 5, 6 and 9 (the so-called SOX trio), NF-κB, EGF and the Th-1-derived cytokine IFN-γ, regulate S100B expression in several cell types [see 7 for review; also see 12]. However, cells that downregulate S100B expression at the onset of their differentiation resume S100B expression at completion of development [7,106], and in mature cells the protein regulate a large variety of key activities including maintenance of shape, transcription, protein degradation, Ca²⁺ homeostasis, energy metabolism and enzyme functions by interacting with a wide array of target proteins. Binding partners of S100B within cells are tubulin and the microtubule-associated τ protein, the actin-binding protein caldesmon, calponin, type III intermediate filament subunits, annexin 6 [7,112-119], membrane-bound guanylate cyclase, the small GTPase Rac1 and Cdc42 effector IQGAP1, Src kinase, the serine/threonine protein kinase Ndr, the tumor suppressor p53, intermediates upstream of IKKβ/NF-κB, the giant phosphoprotein AHNAK/desmoyokin, the E3 ligase hdm2, dopamine D2 receptor and the mitochondrial AAA ATPase, ATAD3A [7,120,121] (Fig. 6). Thus, lack of S100B downregulation may maintain cell proliferation with potential beneficial effects during development and tissue regeneration, and detrimental effects during tumorigenesis. S100B also regulates Ca²⁺ homeostasis [122-125], but opposing results were reported in astrocytes and VSMCs [122,124] (Fig. 6). Moreover, S100B binds to, and inhibits EAG1 potassium channels Ca²⁺-dependently (Fig. 6) raising the possibility that its negative effects on cell differentiation may be via this mechanism as well [125]. Chronically high S100B levels such as those obtained in S100B transgenic mice are proposed to be causally correlated with Parkinson's disease likely via downregulation of dopamine D2 receptor and G protein-coupled receptor kinase2 expression, increased dopamine synthesis and metabolism, and decreased serotonin levels [126] and/or S100B interaction with the third cytoplasmic loop of the dopamine D2 receptor and extracellular signal-regulated kinase (ERK)1/2-mediated inhibition of adenylyl cyclase activity in striatal neurons [127] (Fig. 6). S100B is highly expressed in astrocytes [7] and to a lesser extent in certain neuronal populations [128,129], and its elevation in serum positively correlates with mood disorders [130] and schizophrenia [131]. Serum levels of S100B are of prognostic value in patients with cutaneous melanoma [105] and breast cancer [132]. Whether serum levels of S100B are an outcome predictor in severe traumatic brain injury is a matter of debate [133,134].