ZNF proteiini neurodegeneratiivisissa taudeissa ZNF179 (RNF112, neurolastiini, BFP), ZNF749 (PARIS,parkin interacting) ja ZPR1(ZNF259)

M.Cassandri  (2017) ottaa näistä proteiineista esimerkiksi  ZNF179 ja ZNF746 ja ZPR1 (ZNF259) sinkkisormiproteiinit.
PubMed tietolähde näistä:

• ZNF179, RNF112 (17p11.2),https://www.ncbi.nlm.nih.gov/gene/7732

BFP; ZNF179. This gene encodes a member of the RING finger protein family of transcription factors. The protein is primarily expressed in brain. The gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]. Preferred Names: RING finger protein 112.
Names: brain finger protein,
neurolastin,
zinc finger protein 179.

Related articles in PubMed

1. cDNA cloning of a human brain finger protein, BFP/ZNF179, a member of the RING finger protein family. Seki N, et al. DNA Res, 1999 Oct 29. PMID 10574464
2. The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2. Kimura T, et al. Am J Med Genet, 1997 Mar 31. PMID 9096764
3. Znf179 induces differentiation and growth arrest of human primary glioblastoma multiforme in a p53-dependent cell cycle pathway. Lee KH, et al. Sci Rep, 2017 Jul 6. PMID 28684796, Free PMC Article
4. Neurolastin, a Dynamin Family GTPase, Regulates Excitatory Synapses and Spine Density. Lomash RM, et al. Cell Rep, 2015 Aug 4. PMID 26212327, Free PMC Article  Membrane trafficking and spinogenesis contribute significantly to changes in synaptic strength during development and in various paradigms of synaptic plasticity. GTPases of the dynamin family are key players regulating membrane trafficking. Here, we identify a brain-specific dynamin family GTPase, neurolastin (RNF112/Znf179), with closest homology to atlastin. We demonstrate that neurolastin has functional GTPase and RING domains, making it a unique protein identified with this multi-enzymatic domain organization. We also show that neurolastin is a peripheral membrane protein that localizes to endosomes and affects endosomal membrane dynamics via its RING domain. In addition, neurolastin knockout mice have fewer dendritic spines, and rescue of the wild-type phenotype requires both the GTPase and RING domains. Furthermore, we find fewer functional synapses and reduced paired pulse facilitation in neurolastin knockout mice. Thus, we identify neurolastin as a dynamin family GTPase that affects endosome size and spine density.
5. Molecular cloning, localization, and developmental expression of mouse brain finger protein (Bfp)/ZNF179: distribution of bfp mRNA partially coincides with the affected areas of Smith-Magenis syndrome. Orimo A, et al. Genomics, 1998 Nov 15. PMID 9806830

See all (11) citations in PubMed

GeneRIFs: Gene References Into Functions

Plzf was identified as a specific interacting protein of Znf179; the region containing the first two zinc fingers is critical for its interaction with Znf179. Cellular localization of Znf179 changed from cytoplasm to nucleus when Plzf was co-expressed.

 https://www.ncbi.nlm.nih.gov/pubmed/24359566

Our results showed that Znf179 interacted with Plzf, resulting in its translocation from cytoplasm to the nucleus and increase of Plzf protein abundance. Although the precise nature and role of the Znf179-Plzf interaction remain to be elucidated, both of these two genes are involved in the regulation of neurogenesis. Our finding provides further research direction for studying the molecular functions of Znf179. 

Suomennosta  6.6. 2019 M. Casasndrin artikkelista ( 2017) .
ZNF 179  (neurodegeneratiivisdessa taudissa . Aivospesifinen  dynamiiniperheen GTPaasi neurolastiini RNF112/ZNF179).

"ZNF179 on C4-tyyppinen , ei transkriptiofaktori sinkkisormiproteiini, joka kuuluu RING-finger- alaluokkaan.  Sen ilmentymä on rajoittunut aivoon, mikä viittaisi sen osuuteen keskushermostojärjeselmässä.  Sillä näyttääkin olevan  hermostoon viittaava nimikin: neurolastiini.
ZNF179:n ilmentymän  estäminen  vähentää neuronien erilaistumista, differentioitumista, . P19-soluissa ja pikkuaivojen granulaaristen solujen primaariviljelmässä , koska estyy solusyklin progredioituminen - vlittäviä tekijöitä ovat p35 säätely ja p27-proteiinin kertyminen. Viime aikoina on myös osoitettu ZNF179:n olevan antiapoptoottinen hiiren AD - mallissa , APPTg-astrosyyteissä. Tämä vaikutus johtuu osaksi IGB3:n ja Bik- expressioiden  estymisestä."  

• ZNF746,  PARIS, (7q36.1) (https://www.ncbi.nlm.nih.gov/gene/155061

C4- type  ZNF, non-transcriptional factor.  , KRAB (Krüppel-Associated Box) and ZNF  protein

Preferred Names: zinc finger protein 746.

Names: parkin-interacting substrate,

1. Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells. Kim B, et al. Oncol Rep, 2014 Jan. PMID 24145959
2. Zinc finger protein 746 promotes colorectal cancer progression via c-Myc stability mediated by glycogen synthase kinase 3β and F-box and WD repeat domain-containing 7. Jung JH, et al. Oncogene, 2018 Jul. PMID 29628506
3. SUMOylation of the KRAB zinc-finger transcription factor PARIS/ZNF746 regulates its transcriptional activity. Nishida T, et al. Biochem Biophys Res Commun, 2016 May 13. PMID 27086851
4. Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration. Stevens DA, et al. Proc Natl Acad Sci U S A, 2015 Sep 15. PMID 26324925, Free PMC Article
5. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease. Shin JH, et al. Cell, 2011 Mar 4. PMID 21376232, Free PMC Article A hallmark of Parkinson's disease (PD) is the preferential loss of substantia nigra dopamine neurons. Here, we identify a new parkin interacting substrate, PARIS (ZNF746), whose levels are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human PD brain. PARIS represses the expression of the transcriptional coactivator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons in a PARIS-dependent manner. Moreover, overexpression of PARIS leads to the selective loss of DA neurons in the substantia nigra, and this is reversed by either parkin or PGC-1α coexpression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.

6.6. 2019 : M.Cassandrin tekstin (2017)  suomennosta . ZNF746 neurodegeneratiivisesa taudissa.

" Viime vuosina on havaittu tälle  sinkkisormiproteiinille ZNF746 ,  joka tunnetaan myös nimellä PARIS,  eräs uusi  rooli. PARIS on lyhennys sanoista "parkin interacting substrate".  Parkin on E3 ubikitiiniligaasi,  jonka kohdemolekyli on  tämä PARIS.  Siis parkin johtaa PARIS- proteiinin proteosomisilppuriin.  Ihmisen ZNF746  sisältää C2H2 ja C2H2- tyyppisen  sinkkisormen C-terminaalissa.     Ongelma parkinsonin taudissa on mm.  se, että  mutaatiot  PARK2 -geenissä  johtavat E3-ubikitinaasifunktion katoon, mistä  seuraa  ZNF746- proteiinin kertymää  ihmsen PD taudissa  aivoalueelle. ZNF746:n yli-ilmentyminen johtaa dopaminergisten neuronien katoon substantia nigrasta vaimentamalla PPARgamma-koaktivaattorin PPARgC1A. ( toinen nimi PGC1alfa) Kuva 5a. 

Tämä PGC1alfa (4p15.2)  on tärkeä  normaalin terveyden fysiologiassa,  ja  se välittää vaikutuksia, joit   myös ulkoiset fysiologiset stimulukset kuten energian saanti ja sen käyttö luovat.  Metaboliset taudit ja verenpainekin mainitaan tässä yhteydessä.   https://www.ncbi.nlm.nih.gov/gene/10891

• ZPR1 (11q23.3), https://www.ncbi.nlm.nih.gov/gene/8882

ZNF259. The protein encoded by this gene is found in the cytoplasm of quiescent cells but translocates to the nucleolus in proliferating cells. The encoded protein interacts with survival motor neuron protein (SMN1) to enhance pre-mRNA splicing and to induce neuronal differentiation and axonal growth.
Defects in this gene or the SMN1 gene can cause spinal muscular atrophy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]
Preferred Names: zinc finger protein ZPR1

Names: zinc finger protein 259.

Related articles in PubMed.  (Näissä  allaolevissa  artikkeleissa en havaitse mainintaa SMA1 taudista, joten katson myös  viitteen SMA1 geenistä).

1. Two-stage association study to identify the genetic susceptibility of a novel common variant of rs2075290 in ZPR1 to type 2 diabetes. Guan F, et al. Sci Rep, 2016 Jul 14. PMID 27411854, Free PMC Article
2. Zinc Finger Protein 259 (ZNF259) Polymorphisms are Associated with the Risk of Metabolic Syndrome in a Han Chinese Population. Wu Y, et al. Clin Lab, 2015. PMID 26118197
3. Sex-specific association of the zinc finger protein 259 rs2075290 polymorphism and serum lipid levels. Aung LH, et al. Int J Med Sci, 2014. PMID 24688311, Free PMC Article
4. Association of the variants in the BUD13-ZNF259 genes and the risk of hyperlipidaemia. Aung LH, et al. J Cell Mol Med, 2014 Jul. PMID 24780069, Free PMC Article
5. Effects of apolipoprotein A5 haplotypes on the ratio of triglyceride to high-density lipoprotein cholesterol and the risk for metabolic syndrome in Koreans. Cha S, et al. Lipids Health Dis, 2014 Mar 12. PMID 24618354, Free PMC Article

GeneRIFs: Gene References Into Functions

1. Results suggest that ZPR1 plays an important role in the etiology of type 2 diabetes mellitus, and this gene might be involved in abnormal glucose metabolism.
2. When the inter-dependence between alleles was examined using conditional models, five loci on BUD13, ZNF259, and ApoA5 showed possible independent associations.
3. Single nucleotide polymorphisms (Rs964184, rs3317316, rs6589566) of ZNF259 protein did not increase the risk of CHD in the Chinese population.
4. ZNF259 variants were associated with elevated Metabolic Syndrome risk in a Han Chinese population from the Jilin province of Northeastern China
5. Single nucleotide polymorphism zinc finger protein 259 gene is associated with hyperlipidaemia.
6. Significant linkage disequilibria were noted among ZNF259, BUD13 and MLXIPL SNPs and serum lipid levels.
7. These findings suggest that the association between ZNF259 rs2075290 SNP and serum lipid levels might have ethnic- and/or sex-specificity.
8. Novel APOA5-ZNF259 haplotype manifesting sex-dependent effects on elevation of the TG:HDL-C ratio as well as the increased risk for metabolic syndrome.
9. genetic polymorphism at the loci is associated with Factor VII and fibrinogen levels, and with plasma viscosity
10. Significant associations of two SNPs (rs964184 and rs12286037) from ZNF259 with triglyceride levels in an Asian Indian cohort.

(6.6. 2019 Suomennosta M. Cassandrin tekstistä.)  ZPR1 neurodegeneratiivsessa taudissa:

"Sinkkisormiproteiinien on osoitettu olevan tärkeitä myös  neuraalisten tautien patogeneesissä. SMA, spinaalinen lihasatrofia, on harvinainen tauti, jota luonnehtii alfa-motoristen  neuronien kato selkäytimen  etusarvesta sekä progressiivinen liahsten kuihtuminen. Tauti saataa johtaa usein  varhaiseen menehtymiseen.  Taudin syynä on mutaatio SMN1- geenissä, jonka nimi on Survival Motor Neuron 1.  Mutatoitumisesta johtuu täyspitkän SMN-proteiinin alentunut ilmentymä. SMN-proteiini on välttämätön motoristen neuronien elossapysymiselle. Ensimmäinen näyttö   sinkkisormiproteiinin ZPR1(ZNF259) mahdollisesta osuudesta SMA-tautiin saatiin kokeellisesta havainnosta: Nähtiin SMN-proteiinin tekevän interaktiota  ZPR1:n kanssa. ZPR1 on C4- tyyppinen  sinkkisormiproteiini, joka ei ole transkriptiofaktori. 
Tämän interaktion seurauksena kompleksi sijoitautui uudelleen sytoplasman puolelta tuman puolelle. havaittiin, että tämä prosessi oli haittaantunut 1-tyypin SMA-tautia potevilla.  Havainto sai lisävahvistusta, kun  saatiin osoitettua, että vaikeaa SMA-tautia  sairastavilla oli ZPR1-pitoisuudet matalia. Edelleen  saatiin raporttia hiirikokeista:  ZPR1- mutaatiot aiheuttivat hiirialkioiden kuolleisuutta.  Myös ZPR1-ilmentymän vähenemä tuotti hiirillä lisääntyvää spinaalisten motoristen neuronien katoa, samanlaista fenotyyppiä kuin niillä hiirillä, joiden smn-geeni oli vähentynyt.. Tämä viittaisi siihen, että SMA-potilailla esiintyvistä  matalammista ZPR1- ilmentymistä
 voi seurata vaikutusta SMA-taudin vaikeusasteeseen".
SMA1 tauti on harvinainen. 

SMA1 geenin tilanteen osuus:

Also known as  SMA; SMN; SMA1; SMA2; SMA3; SMA4; SMA@; SMNT; BCD541; GEMIN1; TDRD16A; T-BCD541

Summary  This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric and centromeric copies of this gene are nearly identical and encode the same protein. However, mutations in this gene, the telomeric copy, are associated with spinal muscular atrophy; mutations in the centromeric copy do not lead to disease. The centromeric copy may be a modifier of disease caused by mutation in the telomeric copy. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. The protein encoded by this gene localizes to both the cytoplasm and the nucleus. Within the nucleus, the protein localizes to subnuclear bodies called gems which are found near coiled bodies containing high concentrations of small ribonucleoproteins (snRNPs). This protein forms heteromeric complexes with proteins such as SIP1 and GEMIN4, and also interacts with several proteins known to be involved in the biogenesis of snRNPs, such as hnRNP U protein and the small nucleolar RNA binding protein. Multiple transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2014]

Expression  Ubiquitous expression in bone marrow (RPKM 24.8), testis (RPKM 21.9) and 25 other tissues See more

https://www.ncbi.nlm.nih.gov/pubmed/31138677
 https://www.ncbi.nlm.nih.gov/pubmed/31060440
 https://www.ncbi.nlm.nih.gov/pubmed/30842449