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lördag 16 november 2019

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

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:

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
    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
    Conserved Domains (7) summary
    (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.
    CUB; CUB domain; extracellular domain; present in proteins mostly known to be involved in development; not found in prokaryotes, plants and yeast.
    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 ...
    Kelch; KELCH repeat [structural motif]
    PSI; Plexin repeat
    Kelch_3; Galactose oxidase, central domain
    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
    Atraktiinivajeen merkitys. Tutkimuskoe-eläimeltä:)
    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.


    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.

måndag 11 november 2019

Myelinaatio ja Dyneiini

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.
[Indexed for MEDLINE]
Free PMC Article

torsdag 7 november 2019


Tutkimusten alainen Kelch-superperheen  KBTBD-ryhmän  proteiini , jota  ilmentyy eniten aivoissa, siten kilpirauhasessa ja useissa muissa kudoksissa . https://genecards.weizmann.ac.il/v3/cgi-bin/carddisp.pl?gene=KBTBD3: Funktio pohdittavana.

HGNC Gene Families:

BTBD: BTB/POZ domain containing

Selected InterPro protein domains (see all 7):

 IPR017096 Kelch-like_gigaxonin-typ
 IPR000210 BTB/POZ-like
 IPR006652 Kelch_1
 IPR011333 BTB/POZ_fold
 IPR013069 BTB_POZ

Graphical View of Domain Structure for InterPro Entry Q8NAB2
ProtoNet protein and cluster: Q8NAB2
2 Blocks protein domains:
IPB000210 BTB/POZ domain
IPB011705 BTB/Kelch-associated

UniProtKB/Swiss-Prot: KBTB3_HUMAN, Q8NAB2
Similarity: Contains 1 BACK (BTB/Kelch associated) domain
Similarity: Contains 1 BTB (POZ) domain
Similarity: Contains 5 Kelch repeats

Koetan hahmottaa rakennetta ja verrata esim  gigaxoniin, onko jotain tai mitään  samaa sekvenssipätkää) Kesken...Minkälainen Znf?

Also known as
Ubiquitous expression in brain (RPKM 1.9), thyroid (RPKM 1.3) and 25 other tissues See more
FEATURES             Location/Qualifiers
     source          1..533
                     /organism="Homo sapiens"
     Protein         1..533
                     /product="kelch repeat and BTB domain-containing protein 3
                     isoform 2"
                     /note="BTB and kelch domain containing 3; kelch repeat and
                     BTB domain-containing protein 3; BTB and kelch
                     domain-containing protein 3; kelch repeat and BTB (POZ)
                     domain containing 3; epididymis secretory sperm binding
     Region          16..507
                     /note="Broad-Complex, Tramtrack and Bric a brac; cl28614"
     Region          255..310
                     /region_name="KELCH repeat"
                     /note="KELCH repeat [structural motif]"
     Region          314..362
                     /region_name="KELCH repeat"
                     /note="KELCH repeat [structural motif]"
     Region          365..410
                     /region_name="KELCH repeat"
                     /note="KELCH repeat [structural motif]"
     Region          462..507
                     /region_name="KELCH repeat"
                     /note="KELCH repeat [structural motif]"
     CDS             1..533
                     /note="isoform 2 is encoded by transcript variant 3"
        1 mfevnmkerd dgsvtitnls skavkafldy aytgktkitd dnvemffqls sflqvsflsk
       61 acsdfliksi nlvnclqlls isdsygstsl fdhalhfvqh hfsllfkssd flemnfgvlq
      121 kclesdelnv peeemvlkvv lswtkhnles rqkylphlie kvrlhqlsee tlqdclfnee
      181 sllkstncfd iimdaikcvq gsgglfpdar psttekyifi hkteengenq ytfcyniksd
      241 swkilpqshl idlpgsslss ygekifltgg ckgkccrtvr lhiaesyhda tdqtwcycpv
      301 kndfflvstm ktprtmhtsv maldrlfvig gktrgsrdik slldvesynp lskewisvsp
      361 lprgiyypea stcqnviyvl gseveitdaf npsldcffky nattdqwsel vaefgqffha
      421 tlikavpvnc tlyicdlsty kvysfcpdtc vwkgegsfec agfnagaigi edkiyilggd
      481 yapdeitdev qvyhsnrsew eevspmpral tefycqviqf nkyrdpwfsn lca


        1 maegsavsdp qhaarllral ssfreesrfc dahlvldgee ipvqknilaa aspyirtkln
       61 ynppkddgst ykielegisv mvmreildyi fsgqirlned tiqdvvqaad lllltdlktl
      121 cceflegcia aencigirdf alhyclhhvh ylateyleth frdvssteef lelspqklke
      181 visleklnvg neryvfeavi rwiahdteir kvhmkdvmsa lwvsgldssy lreqmlnepl
      241 vreivkecsn iplsqpqqge amlanfkprg ysecivtvgg eervsrkpta amrcmcplyd
      301 pnrqlwiela plsmprinhg vlsaegflfv fggqdenkqt lssgekydpd antwtalppm
      361 nearhnfgiv eidgmlyilg gedgekelis mecydiyskt wtkqpdltmv rkigcyaamk
      421 kkiyamgggs ygklfesvec ydprtqqwta icplkerrfg avacgvamel yvfggvrsre
      481 daqgsemvtc ksefyhdefk rwiylndqnl cipasssfvy gavpigasiy vigdldtgtn
      541 ydyvrefkrs tgtwhhtkpl lpsdlrrtgc aalrianckl frlqlqqglf rirvhsp

onsdag 6 november 2019

ACLY entsyymi kolinergisessä neuronissa ym. (2019)

2019 Apr;568(7753):571-575. doi: 10.1038/s41586-019-1095-5. Epub 2019 Apr 3.

Structure of ATP citrate lyase (ACLY)  and the origin of citrate synthase(CS)  in the Krebs cycle.

1Unit for Structural Biology, VIB Center for Inflammation Research, Ghent, Belgium.
2Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.3European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o DESY, Hamburg, Germany.4University of Grenoble Alpes, CNRS, CEA, CNRS, IBS, Grenoble, France.5Integrated Molecular Plant Physiology Research, Department of Biology, University of Antwerp, Antwerp, Belgium.6Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.7Unit for Structural Biology, VIB Center for Inflammation Research, Ghent, Belgium. kenneth.verstraete@ugent.be.8Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium. kenneth.verstraete@ugent.be.


Across different kingdoms of life, ATP citrate lyase (ACLY, also known as ACL) catalyses the ATP-dependent and coenzyme A (CoA)-dependent conversion of citrate, a metabolic product of the Krebs cycle, to oxaloacetate and the high-energy biosynthetic precursor acetyl-CoA1. The latter fuels pivotal biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine2, and the acetylation of histones and proteins3,4. In autotrophic prokaryotes, ACLY is a hallmark enzyme of the reverse Krebs cycle (also known as the reductive tricarboxylic acid cycle), which fixates two molecules of carbon dioxide in acetyl-CoA5,6. In humans, ACLY links carbohydrate and lipid metabolism and is strongly expressed in liver and adipose tissue1 and in cholinergic neurons2,7.

 The structural basis of the function of ACLY remains unknown. Here we report high-resolution crystal structures of bacterial, archaeal and human ACLY, and use distinct substrate-bound states to link the conformational plasticity of ACLY to its multistep catalytic itinerary. Such detailed insights will provide the framework for targeting human ACLY in cancer8,9,10,11 and hyperlipidaemia12,13. Our structural studies also unmask a fundamental evolutionary relationship that links citrate synthase, the first enzyme of the oxidative Krebs cycle, to an ancestral tetrameric citryl-CoA lyase module that operates in the reverse Krebs cycle. This molecular transition marked a key step in the evolution of metabolism on Earth.

KLHL25(ENC-2) ja ATP:sitraattilyaasi ACLY

 Kelch- superperheen proteiini KLHL25 toimii adaptorina kun CUL3  johtaa ATP:sitraattilyaasia proteosomisilppuriin. 

Entä miten nämä toimivat aivossa?
Aivossa tarvitaan  jatkuvaa rasva-aine ja kolesterolisynteesiä, koska aivo on  rasvamoduli, koostunut hyvin monimutkaisista j monipuolisista lipidiaineista.  Lisäksi neuronit tarvitsevat AcetylCoaa  muodostamaan hermonvälittäjäainetta asetylkoliinia kolinergisessä järjestelmässä. Se toimii eräänlaisena clearing-tekijänä   hermoissa ja  varsinkin tahdonalaisessa ajattelussa ja toiminnassa se on tärkeä.   hermorata. Löytyykö jotain konkreettista karttaa  sitraatista, kelch-proteiinifunktiosta,  ja yhteydestä muihin  elementaarisiin etikkahapon ja sitruunahapon tasoa kuvaaviin kaavoihin?

Cullin3KLHL25 ubiquitin ligase targetsACLY for degradation to inhibit lipidsynthesis and tumor progression

 Cen Zhang,1,4Juan Liu,1,4Grace Huang,2Yuhan Zhao,1Xuetian Yue,1Hao Wu,1Jun Li,1Junlan Zhu,2Zhiyuan Shen,1Bruce G. Haffty,1Wenwei Hu,1and Zhaohui Feng1,31Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State Universityof New Jersey, New Brunswick, New Jersey 08903, USA;2Nelson Institute of Environmental Medicine, New York UniversitySchool of Medicine, New York University, Tuxedo, New Jersey 10987, USA;3Department of Pharmacology, Rutgers University,The State University of New Jersey, Piscataway, New Jersey 08854, USA

 Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citratelyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipidsynthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate anddegrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation,and xenograft tumor growth of lung cancer cells. Furthermore, ACLY inhibitor SB-204990 greatly abolishes thepromoting effect of CUL3 down-regulation on lipid synthesis, cell proliferation, and tumor growth. Importantly, lowCUL3 expression is associated with high ACLY expression and poor prognosis in human lung cancer. In summary,our results identify CUL3KLHL25 ubiquitin ligase as a novel negative regulator for ACLY and lipid synthesis anddemonstrate that decreased CUL3 expression is an important mechanism for increased ACLY expression and lipidsynthesis in lung cancer. These results also reveal that negative regulation of ACLY and lipid synthesis is a novel andcritical mechanism for CUL3 in tumor suppression.[Keywords: CUL3; ACLY; KLHL25; ubiquitination; lipid synthesis; tumor 

 Image result for citrate synthase,  citrate lyase


SIRT3 have been found to be neuroprotective in many neurological diseases, but its detail mechanism is only partially understood. In this study, MPP+ was used to treat SH-SY5Y cells as the cellular model of PD to test the role of SIRT3 and the mechanism may be involved in. We focused on the changes and relationship between SIRT3 and the key mitochondrial enzymes citrate synthase (CS) and isocitrate dehydrogenase 2 (IDH2). We found MPP+ decreased SIRT3 expression. And our results showed that the enzymatic activities of CS and IDH2 were significantly reduced in MPP+ treatment cells, while protein acetylation of CS and IDH2 increased. However overexpressed-SIRT3 partially reversed at least, the decline of CS activity and the increase of CS protein acetylation. IDH2 did not showed the same changes. The study suggested that SIRT3 deacetylated and activated CS activity. Hence, we conclude that SIRT3 exhibits neuroprotection via deacetylating and increasing mitochondrial enzyme activities.
Deacetylation; Enzyme activity; Mitochondria; Neuroprotection; Parkinson disease; SIRT3



ENC-1 (KLHL37) (5q13.3) Tumamatrixproteiini aivoissa, rajoittaa NRF2:n translatoitumista.


Also known as
NRPB; CCL28; ENC-1; PIG10; KLHL35; KLHL37; TP53I10
This gene encodes a member of the kelch-related family of actin-binding proteins. The encoded protein plays a role in the oxidative stress response as a regulator of the transcription factor Nrf2, and expression of this gene may play a role in malignant transformation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]
Biased expression in brain (RPKM 180.1), gall bladder (RPKM 11.8) and 4 other tissues See more

KLHL16 (16q23.2), Gigaxoniini, GAN . Mutaatioiden merkitys.


Edellisen KLHL1 geenin löytöä  käsittelevän  tekstin sitaatissa oli seuraavat lauseet:  

..."The Kelch-related proteins have diverse functions in cell morphology, cell organization, and gene expression, and function in multiprotein complexes through contact sites in their β-propeller domains (14). Recently, a new member of the BTB/Kelch repeat family, gigaxonin (GAN, KLHL16), was reported to be a pathological target for neurodegenerative disorders in which alterations were found to contain multiple mutations in the Kelch repeats in the neurofilament network (15)." tarkistan viitteen 15:


The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy


Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease1,2,3,4. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons5,6. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes7,8,9,10,11. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs12.

 We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a β-propeller shape13. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.