Prion Protein
Prions

GPI anchor and CD14

Sphingolipid deficiency induces hypersensitivity of CD14, a glycosyl phosphatidylinositol-anchored protein, to phosphatidylinositol-specific phospholipase C. 1993

Bate C, Tayebi M, Salmona M, Diomede L, Williams A [new window][clusters][order now]
Polyunsaturated Fatty Acids Protect Against Prion-Mediated Synapse Damage In Vitro.
Neurotox Res. 2009 Jul 31 [Epub ahead of print].

[...] hippocampal neurones incubated with the disease associated isoform of the prion protein (PrP), or with the prion-derived peptide PrP82-146. The addition of PrP [...]

Therapy by increased autophagy

Papers autophagy prion

Picture Autophagy

Autophagy, Prion Infection and their Mutual Interactions 2009

Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies 2008

J Neurochem. 2009 Apr;109(1):25-34. Epub 2009 Feb 20.Click here to read Links
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Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy.
Heiseke A, Aguib Y, Riemer C, Baier M, Schätzl HM.

Institute of Virology, Technische Universität München, Munich, Germany.

Lithium is used for several decades to treat manic-depressive illness (bipolar affective disorder). Recently, it was found that lithium induces autophagy, thereby promoting the clearance of mutant huntingtin and alpha-synucleins in experimental systems. We show here for the first time that lithium significantly reduces the amount of pathological prion protein (PrP) in prion-infected neuronal and non-neuronal cultured cells by inducing autophagy. Treatment of prion-infected cells with 3-methyladenine, a potent inhibitor of autophagy, counteracted the anti-prion effect of lithium, demonstrating that induction of autophagy mediates degradation of PrP. Co-treatment with lithium and rapamycin, a drug widely used to induce autophagy, had an additive effect on PrP clearance compared to treatment with either drug alone. In addition, we provide evidence that the ability to reduce PrP and to induce autophagy is common for diverse lithium compounds, not only for the drug lithium chloride, usually administered in clinical therapy. Furthermore, we show here that besides reduction of PrP-aggregates, lithium-induced autophagy also slightly reduces the levels of cellular prion protein. Limiting the substrate available for conversion of cellular prion protein into PrP may provide an additional mechanism for reduction of PrP by lithium-induced autophagy.

Prion and RNA

RNA dynamics: it is about time 2008
Riboswitches: small-molecule recognition by gene regulatory RNAs, 2007

G e EQ P simili

SWISSPROT:RL35A_AERPE

RecName: Full=50S ribosomal protein L35Ae; [Aeropyrum pernix]

Translation termination efficiency can be regulated in Saccharomyces cerevisiae by environmental stress through a prion-mediated mechanism. 1999
[PSI+] is a protein-based heritable phenotype of the yeast Saccharomyces cerevisiae which reflects the prion-like behaviour of the endogenous Sup35p protein release factor. [PSI+] strains exhibit a marked decrease in translation termination efficiency, which permits decoding of translation termination signals and, presumably, the production of abnormally extended polypeptides.

RNA and CuCl2 induced conformational changes of the recombinant ovine prion protein 2006

Epigenetic Role of Prions

Prions in Information Storage and Long Term Memory

Small, highly structured RNAs participate in the conversion of human recombinant PrP to PrP in vitro. 2003
J Mol Biol. 2003 Sep 5;332(1):47-57. Links
Adler V, Zeiler B, Kryukov V, Kascsak R, Rubenstein R, Grossman A.

We have identified a small, highly structured (shs)RNA that binds human recombinant prion protein (hrPrP) with high affinity and specificity under physiological conditions (e.g. 10% bovine calf serum (BCS), neutral pH, nanomolar concentrations of RNA and hrPrP). We also demonstrate the ability of this shsRNA to form highly stable nucleoprotein complexes with hrPrP and cellular PrP (PrP©) from various cell extracts and mammalian brain homogenates. The apparent mass of the nucleoprotein complex is dependent on the molar ratio of hrPrP to RNA during complex formation. The hrPrP in these complexes acquires resistance to degradation by Proteinase K (PK). Other shsRNAs, however, under identical conditions, neither form stable complexes with hrPrP nor do they induce resistance to PK digestion. We also demonstrate that the RNAs in these nucleoprotein complexes become resistant to ribonuclease A hydrolysis. These interactions between shsRNAs and hrPrP suggest possible roles of RNAs in the modulation of PrP structure and perhaps disease development. ShsRNAs that bind to hrPrP with high affinity and induce resistance to PK digestion can be used to develop molecular biology assays for the screening of compounds associated with PrP structure transformation or for drugs that inhibit this process.

The peculiar interaction between mammalian prion protein and RNA 2008

Therapy by increased autophagy

Papers autophagy prion

Scrapie-induced defects in learning and memory of transgenic mice expressing anchorless prion protein are associated with alterations in the gamma aminobutyric acid-ergic pathway. 2008;

Prion Iron

Abnormal Brain Iron Homeostasis in Human and Animal Prion Disorders 2009

Mol Biol Cell. 2007 Sep;18(9):3302-12. Epub 2007 Jun 13.Click here to read Click here to read Links
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Modulation of proteinase K-resistant prion protein in cells and infectious brain homogenate by redox iron: implications for prion replication and disease pathogenesis. 2007
Basu S, Mohan ML, Luo X, Kundu B, Kong Q, Singh N.

Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.

The principal infectious and pathogenic agent in all prion disorders is a beta-sheet-rich isoform of the cellular prion protein (PrP©) termed PrP-scrapie (PrP). Once initiated, PrP is self-replicating and toxic to neuronal cells, but the underlying mechanisms remain unclear. In this report, we demonstrate that PrP© binds iron and transforms to a PrP-like form (*PrP) when human neuroblastoma cells are exposed to an inorganic source of redox iron. The *PrP thus generated is itself redox active, and it induces the transformation of additional PrP©, simulating *PrP propagation in the absence of brain-derived PrP. Moreover, limited depletion of iron from prion disease-affected human and mouse brain homogenates and scrapie-infected mouse neuroblastoma cells results in 4- to 10-fold reduction in proteinase K (PK)-resistant PrP, implicating redox iron in the generation, propagation, and stability of PK-resistant PrP. Furthermore, we demonstrate increased redox-active ferrous iron levels in prion disease-affected brains, suggesting that accumulation of PrP is modulated by the combined effect of imbalance in brain iron homeostasis and the redox-active nature of PrP. These data provide information on the mechanism of replication and toxicity by PrP, and they evoke predictable and therapeutically amenable ways of modulating

Infectious Prions Hitch Ride on Ferritin 2005

: J Neurosci. 2004 Dec 15;24(50):11280-90.Click here to read Links
Click here to read"Protease-resistant human prion protein and ferritin are cotransported across Caco-2 epithelial cells: implications for species barrier in prion uptake from the intestine. 2004":http://www.ncbi.nlm.nih.gov/pubmed/15601934?ordinalpos=16&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Mishra RS, Basu S, Gu Y, Luo X, Zou WQ, Mishra R, Li R, Chen SG, Gambetti P, Fujioka H, Singh N.

Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.

Foodborne transmission of bovine spongiform encephalopathy (BSE) to humans as variant Creutzfeldt-Jakob disease (CJD) has affected over 100 individuals, and probably millions of others have been exposed to BSE-contaminated food substances. Despite these obvious public health concerns, surprisingly little is known about the mechanism by which PrP-scrapie (PrP), the most reliable surrogate marker of infection in BSE-contaminated food, crosses the human intestinal epithelial cell barrier. Here we show that digestive enzyme (DE) treatment of sporadic CJD brain homogenate generates a C-terminal fragment similar to the proteinase K-resistant PrP core of 27-30 kDa implicated in prion disease transmission and pathogenesis. Notably, DE treatment results in a PrP-protein complex that is avidly transcytosed in vesicular structures across an in vitro model of the human intestinal epithelial cell barrier, regardless of the amount of endogenous PrP© expression. Unexpectedly, PrP is cotransported with ferritin, a prominent component of the DE-treated PrP-protein complex. The transport of PrP-ferritin is sensitive to low temperature, brefeldin-A, and nocodazole treatment and is inhibited by excess free ferritin, implicating a receptor- or transporter-mediated pathway. Because ferritin shares considerable homology across species, these data suggest that PrP-associated proteins, in particular ferritin, may facilitate PrP uptake in the intestine from distant species, leading to a carrier state in humans.

A Mechanism for Copper Inhibition of Infectious Prion Conversion 2006

Prion Vitamin D

Assessment of calcium-binding proteins (Parvalbumin and Calbindin D-28K) and perineuronal nets in normal and scrapie-affected adult sheep brains. 2006

1. FUNCTION: In muscle, the calcium-binding protein parvalbumin is thought to be involved in muscle relaxation.
2. MASS SPECTROMETRY: Mass=11927; Mass_error=0.76; Method=Electrospray; Range=2-110; Source=PubMed:10036163;
3. MISCELLANEOUS: This protein binds two calcium ions.
4. SIMILARITY: Belongs to the parvalbumin family.
5. SIMILARITY: Contains 2 EF-hand domains.

Papers lysosomes prion

Papers chloroquine prion

Accumulation of prion protein in muscle fibers of experimental chloroquine myopathy: in vivo model for deposition of prion protein in non-neuronal tissues. 2004

Papers Statin prion

1: Vet Microbiol. 2007 Aug 31;123(4):377-86. Epub 2007 Apr 8.Click here to read Links
Strategies for eliminating PrP© as substrate for prion conversion and for enhancing PrP degradation.
Gilch S, Nunziante M, Ertmer A, Schätzl HM.

Institute of Virology, Prion Research Group, Technical University of Munich, Trogerstr. 30, 81765 Munich, Germany.

Prion diseases are fatal neurodegenerative infectious disorders for which no therapeutic or prophylactic regimens exist. Our work aims to eliminate PrP© as substrate for the conversion into PrP and to increase the cellular clearance capacity of PrP. In order to achieve the first objective, we used chemical compounds which interfere with the subcellular trafficking of PrP©, e.g. by intracellular re-routing. Recently, we found that PrP© requires cholesterol for cell surface localisation. Treatment with mevinolin significantly reduced the amount of cell surface PrP© and led to its accumulation in the Golgi compartment. These data show that cholesterol is essential for the cell surface localisation of PrP©, which is in turn known to be necessary for the formation of PrP. Another anti-prion strategy uses RNA and peptide aptamers directed against PrP©. We have selected peptide aptamers using a constrained peptide library presented on the active site loop of the Escherichia coli protein TrxA in a Y2H screen. Several peptides reproducibly binding to PrP© in several assays were identified. Preliminary data indicate that selected peptide aptamers are able to interfere with prion propagation in prion-infected cells. To obtain additive effects we have tried to clarify cellular mechanisms that enable cells to clear prion infectivity. This goal was achieved by selective interference in intracellular signalling pathways which apparently also increase the cellular autophagy machinery. Finally, we have tried to establish an active auto-vaccination approach directed against PrP, which gave some positive preliminary results in the mouse system. This might open the door to classical immunological interference techniques.

Cholesterol synthesis inhibitor U18666A and the role of sterol metabolism and trafficking in numerous pathophysiological processes. 2009

Microbiol Immunol. 2008 Jul;52(7):357-65.Click here to read Links
Synthetic fibril peptide promotes clearance of scrapie prion protein by lysosomal degradation.
Okemoto-Nakamura Y, Yamakawa Y, Hanada K, Tanaka K, Miura M, Tanida I, Nishijima M, Hagiwara K.

Department of Biochemistry and Cell Biology, National Institue of Infectious Diseases, Tokyo, Japan.

Transmissible spongiform encephalopathies are infectious and neurodegenerative disorders that cause neural deposition of aggregates of the disease-associated form of PrP. PrP reproduces by recruiting and converting the cellular PrP©, and ScN2a cells support PrP propagation. We found that incubation of ScN2a cells with a fibril peptide named P9, which comprises an intrinsic sequence of residues 167-184 of mouse PrP©, significantly reduced the amount of PrP in 24 hr. P9 did not affect the rates of synthesis and degradation of PrP©. Interestingly, immunofluorescence analysis showed that the incubation of ScN2a cells with P9 induced colocalization of the accumulation of PrP with cathepsin D-positive compartments, whereas the accumulation of PrP in the cells without P9 colocalized mainly with lysosomal associated membrane proteins (LAMP)-1-positive compartments but rarely with cathepsin D-positive compartments in perinuclear regions. Lysosomal enzyme inhibitors attenuated the anti-PrP activity; however, a proteasome inhibitor did not impair P9 activity. In addition, P9 neither promoted the ubiquitination of cellular proteins nor caused the accumulation of LC3-II, a biochemical marker of autophagy. These results indicate that P9 promotes PrP redistribution from late endosomes to lysosomes, thereby attaining PrP degradation.

Eur J Cell Biol. 2009 Jan;88(1):45-63. Epub 2008 Oct 1.Click here to read Links
Immunolocalisation of PrPSc in scrapie-infected N2a mouse neuroblastoma cells by light and electron microscopy.
Veith NM, Plattner H, Stuermer CA, Schulz-Schaeffer WJ, Bürkle A.

Molecular Toxicology, Department of Biology, University of Konstanz, Box X911, D-78457 Konstanz, Germany.

The causative agent of transmissible spongiform encephalopathies (TSE) is PrPSc, an infectious, misfolded isoform of the cellular prion protein (PrPC). The localisation and trafficking of PrPSc and sites of conversion from PrPC to PrPSc are under debate, particularly since most published work did not discriminate between PrPC and PrPSc. Here we describe the localisation of PrPC and PrPSc in a scrapie-infected neuroblastoma cell line, ScN2a, by light and electron microscopic immunolocalisation. After eliminating PrPC with proteinase K, PrPSc was detected at the plasma membrane, endocytosed via clathrin-coated pits and delivered to early endosomes. Finally, PrPSc was detected in late endosomes/lysosomes. As we detected PrPSc at the cell surface, in early endosomes and in late endosomes/lysosomes, i.e. locations where PrPC is also present, our data imply that the conversion process could take place at the plasma membrane and/or along the endocytic pathway. Finally, we observed the release of PrPC/PrPSc via exocytotic pathways, i.e. via exosomes and as an opaque electron-dense mass which may represent a mechanism of intercellular spreading of infectious prions.

Vet Immunol Immunopathol. 2009 Jul 7. [Epub ahead of print]Click here to read Links
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Bovine macrophage degradation of scrapie and BSE PrP.
Sassa Y, Inoshima Y, Ishiguro N.

Laboratory of Food and Environmental Hygiene, Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-city, Gifu, 501-1193, Japan.

Transmissible spongiform encephalopathies (TSEs), such as bovine spongiform encephalopathy (BSE) and scrapie, display long incubation periods before PrP accumulates in the central neuronal system (CNS). The precise role that phagocytic cells, such as macrophages, play in prion pathogenesis is uncertain. In this study, the involvement of bovine macrophages at the early stage of prion infection was studied. Brain homogenates of mouse scrapie and BSE were degraded sequentially in the bovine macrophage cell line, Bo120, and freshly prepared in monocyte-derived macrophages from peripheral blood. Mouse scrapie brain homogenates degraded in Bo120 cells were inoculated intraperitoneally to C57BL mice, showing that the degree of cellular degradation (2h, 10, 28, and 36d) correlated with survival periods (288, 303, 324, and 340d, respectively). Partial colocalizations of PrP and lysosomes were observed in Bo120 cells by confocal microscopy. These results suggest that bovine macrophages have the ability to take up and degrade PrP, resulting in decreased TSE infectivity in mice.

Cobalt Carrier in Archea

ID CBIN_HALSA Reviewed; 96 AA.
96
A 9 0.094
C 0 0.000
D 5 0.052
E 3 0.031
F 4 0.042
G 15 0.156
H 0 0.000
I 8 0.083
K 0 0.000
L 9 0.094
M 2 0.021
N 2 0.021
P 6 0.063
Q 4 0.042
R 4 0.042
S 9 0.094
T 4 0.042
V 5 0.052
W 4 0.042
Y 3 0.031
X 0 0.000
B 0 0.000
Z 0 0.000
J 0 0.000
O 0 0.000
U 0 0.000
EQ 0.750 0.750
EP 0.500 0.500
YF 0.750 0.750
DN 2.500 2.500
ZQ 0.000 0.000
ZP 0.000 0.000
GS 1.667 1.667

The prion protein and lipid rafts (Review)
Authors: David R. Taylor a; Nigel M. Hooper a
Affiliation: a Proteolysis Research Group, Leeds Institute of Genetics, Health and Therapeutics, Faculty of Biological Sciences, University of Leeds, Leeds, UK
DOI: 10.1080/09687860500449994
Publication Frequency: 8 issues per year
Published in: journal Molecular Membrane Biology, Volume 23, Issue 1 January 2006 , pages 89 - 99
Subjects: Cell Biology; Molecular Biology;
Formats available: HTML (English) : PDF (English)
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Abstract
Prions are the causative agent of the transmissible spongiform encephalopathies, such as Creutzfeldt-Jakob disease in humans. In these prion diseases the normal cellular form of the prion protein (PrPC) undergoes a post-translational conformational conversion to the infectious form (PrPSc). PrPC associates with cholesterol- and glycosphingolipid-rich lipid rafts through association of its glycosyl-phosphatidylinositol (GPI) anchor with saturated raft lipids and through interaction of its N-terminal region with an as yet unidentified raft associated molecule. PrPC resides in detergent-resistant domains that have different lipid and protein compositions to the domains occupied by another GPI-anchored protein, Thy-1. In some cells PrPC may endocytose through caveolae, but in neuronal cells, upon copper binding to the N-terminal octapeptide repeats, the protein translocates out of rafts into detergent-soluble regions of the plasma membrane prior to endocytosis through clathrin-coated pits. The current data suggest that the polybasic region at its N-terminus is required to engage PrPC with a transmembrane adaptor protein which in turn links with the clathrin endocytic machinery. PrPC associates in rafts with a variety of signalling molecules, including caveolin-1 and Fyn and Src tyrosine kinases. The clustering of PrPC triggers a range of signal transduction processes, including the recruitment of the neural cell adhesion molecule to rafts which in turn promotes neurite outgrowth. Lipid rafts appear to be involved in the conformational conversion of PrPC to PrPSc, possibly by providing a favourable environment for this process to occur and enabling disease progression.
Keywords: Cholesterol; detergent-resistant membrane; glycosyl-phosphatidylinositol; lipid raft; prion protein

J Neuropathol Exp Neurol. 2009 Aug;68(8):870-9.
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Reduction of prion infectivity and levels of scrapie prion protein by lithium aluminum hydride: implications for RNA in prion diseases.

Jeong BH, Kim NH, Jin JK, Choi JK, Lee YJ, Kim JI, Choi EK, Carp RI, Kim YS.

Ilsong Institute of Life Science, Hallym University, Gyounggi-do, South Korea.

Previous studies indicate that RNA may be required for proteinase-resistant prion protein (PrP) amplification and for infectious prion formation in vitro , suggesting that RNA molecules may function as cellular cofactors for abnormal PrP (PrPSc) formation and become part of the structure of the infectious agent. To address this question, we used chemicals that can cleave phosphodiester bonds of RNA and assessed their effects on the infectious agent. Lithium aluminum hydride, a reducing agent that can induce reductive cleavage of oxidized molecules such as carbonyls, carboxyl acids, esters, and phosphodiester bonds, did not affect cellular PrP degradation; however, it destroyed PrPSc, extended the scrapie incubation period, and markedly reduced total RNA concentrations. These results prompted us to investigate whether RNA molecules are cofactors for PrPSc propagation. RNase A treatment of partially purified PrP and of 263K scrapie brain homogenates was sufficient to increase the sensitivity of PrPSc to proteinase K degradation. This is the first evidence that suggests that RNA molecules are a component of PrPSc. Treatment with RNase A alone and PrP degradation by RNase A plus proteinase K in vitro, however, did not result in loss of scrapie infectivity compared with the effects of lithium aluminum hydride. Together, these data suggest that RNA molecules may be important for maintaining the structure of PrPSc and that oxidized molecules can be important in scrapie agent replication and prion infectivity.

J Neurochem. 2007 Jun;101(6):1516-26.Click here to read Links
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Selective re-routing of prion protein to proteasomes and alteration of its vesicular secretion prevent PrP formation.
Filesi I, Cardinale A, Mattei S, Biocca S.

Department of Neuroscience and Laboratory of Clinical Biochemistry, University of Tor Vergata, Rome, Italy.

Conversion of the cellular prion protein (PrP©) into the abnormal scrapie isoform (PrP) is the hallmark of prion diseases, which are fatal and transmissible neurodegenerative disorders. ER-retained anti-prion recombinant single-chain Fv fragments have been proved to be an effective tool for inhibition of PrP© trafficking to the cell surface and antagonize PrP formation and infectivity. In the present study, we have generated the secreted version of 8H4 intrabody (Sec-8H4) in order to compel PrP© outside the cells. The stable expression of the Sec-8H4 intrabodies induces proteasome degradation of endogenous prion protein but does not influence its glycosylation profile and maturation. Moreover, we found a dramatic diverting of PrP© traffic from its vesicular secretion and, most importantly, a total inhibition of PrP accumulation in NGF-differentiated Sec-8H4 PC12 cells. These results confirm that perturbing the intracellular traffic of endogenous PrP© is an effective strategy to inhibit PrP accumulation and provide convincing evidences for application of intracellular antibodies in prion diseases.

Neurochem Res. 2004 Mar;29(3):493-504.Click here to read Links
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Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance.

Rossi L, Lombardo MF, Ciriolo MR, Rotilio G.

Department of Biology, "Tor Vergata" University of Rome, Via della Ricerca Scientifica, 00133 Rome, Italy.

Copper is an essential transition metal ion for the function of key metabolic enzymes, but its uncontrolled redox reactivity is source of reactive oxygen species. Therefore a network of transporters strictly controls the trafficking of copper in living systems. Deficit, excess, or aberrant coordination of copper are conditions that may be detrimental, especially for neuronal cells, which are particularly sensitive to oxidative stress. Indeed, the genetic disturbances of copper homeostasis, Menkes' and Wilson's diseases, are associated with neurodegeneration. Furthermore, copper interacts with the proteins that are the hallmarks of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, prion diseases, and familial amyotrophic lateral sclerosis. In all cases, copper-mediated oxidative stress is linked to mitochondrial dysfunction, which is a common feature of neurodegeneration. In particular we recently demonstrated that in copper deficiency, mitochondrial function is impaired due to decreased activity of cytochrome c oxidase, leading to production of reactive oxygen species, which in turn triggers mitochondria-mediated apoptotic neurodegeneration.

HOW DO INTRACELLULAR PROTEOLYTIC SYSTEMS CHANGE WITH AGE? 1998

HORN_HUMAN famiglia s100 assomiglia PrP
RBP56_HUMAN Belongs to the RNA polymerase II (Pol II) transcriptional multiprotein complex,
FILA2_HUMAN S100The human intermediate filament-associated protein family.
CD2A2_HUMAN Full=Cyclin-dependent kinase inhibitor 2A, isoform 4;
C1QA_HUMAN Complement C1q subcomponent subunit A; no met hist trp
MARCO_HUMAN Full=Macrophage receptor MARCO; AltName: Full=Macrophage receptor with collagenous structure
LSM4_HUMAN U6 snRNA-associated Sm-like protein LSm4;
TWST1_HUMAN Full=Twist-related protein 1; AltName: Full=H-twist; [Homo sapiens (Human)]
TNFC_HUMAN Full=Lymphotoxin-beta; Short=LT-beta; AltName: Full=Tumor necrosis factor C

Phenotyping of Protein–Prion (PrPsc)-accumulating Cells in Lymphoid and Neural Tissues of Naturally Scrapie-affected Sheep by Double-labeling Immunohistochemistry 2002 S110

DMKN_HUMAN dermokine family keratinocytes
Papers keratinocytes prion

Papers wilson disease prion