Role of amyloids in HIV and XMRV transmission and pathogenesis

[George]

An interesting tidbit I found when I was diggin' around.

http://www.doktorandenboerse.info/suchen/angebot_ausgabe.php?Angebot_id=5746&Uni=33&Fach=,1,3,

Universitt: Universitt - Ulm
Fach / Institut: Virologie
Abteilung: Institute of Molecular Virology
Gesucht werden: Doktoranden
aus den Bereichen: Medizin, Biologie
Art der Arbeit: experimentell

Role of amyloids in HIV and XMRV transmission and pathogenesis​

Our group demonstrated that amyloid aggregates in semen play an important role in the sexual transmission of HIV-1 (Cell. 2007, 131:1059-71) and, more recently, of XMRV, a novel human retrovirus associated with prostate cancer and chronic fatigue syndrome (J Virol. 2009, 83:6995-7003). The goal of the research project is to analyze the effect of amyloid structures recently identified from prostate and semen on XMRV and HIV infection. Therefore we are seeking for two Ph.D. students who will analyze the virus enhancing effect, the underlying mechanism and the implications for virus infection, transmission, pathogenesis and eventually tumour development. (well that's interesting, scratching head)

The research project includes a broad variety of methods from different disciplines like work with infectious viruses under BSL3 conditions, isolation and culture of primary cells and tissues, flow cytometry, immunofluorescence, laser scanning and confocal microscopy, qRT-PCR, blotting techniques, reporter gene assays, amyloid generation, electron microscopy, as well as cloning techniques.

We are looking for two highly motivated and ambitious PhD students with a strong background in molecular biology, virology, amyloids or related areas of research. Willingness for teamwork is a prerequisite.

We offer a highly interactive and innovative and state of the art equipped research environment located in the novel Institute of Molecular Virology headed by Prof. Dr. Frank Kirchhoff. Our international research team currently consists out of 20 PhD students, PostDocs and technicians. Our work has received various research awards and resulted in high ranked publications. The positions are funded by the Landesstiftung Baden-Wrttemberg (TV-L E13/2).

The University Ulm supports women in science and especially encourages them to apply. Handicapped applicants with equal qualifications will be preferred.

Your application should include a cover letter, CV and copies of the most important certificates and a letter of recommendation. It can be send by mail or by e-mail. We are looking forward to your application!

Prof. Dr. Jan Mnch
Institute of Molecular Virology
University Hospital Ulm
Meyerhofstrae 1
89081 Ulm
Germany
phone: ++49 731 500 65154
fax: ++49 731 500 65167
jan.muench@uni-ulm.de

 

[lansbergen]

Boy, this is good. Makes me happy.

 

[lansbergen]

http://jvi.asm.org/cgi/content/abstract/83/14/6995

Fibrils of Prostatic Acid Phosphatase Fragments Boost Infections with XMRV (Xenotropic Murine Leukemia Virus-Related Virus), a Human Retrovirus Associated with Prostate Cancer{triangledown}

 

[DysautonomiaXMRV]

Good find George!

Some more info from Phoenix Rising on Amyloid and CFS/XMRV.

http://aboutmecfs.org/Rsrch/XMRVPuppetMaster.aspx
2nd paragraph from bottom

http://phoenix-cfs.org/old_site/PRDec05.htm
1/4 down the page on the right - Cerebral Amyloid Angiopathies


And look where else Amyloid turns up in this study...........

A chronic fatigue syndrome - related proteome in human cerebrospinal fluid.
Baraniuk, JN., Casado, B., Maibach, H., Clauw, DJ., Pannell, LK and Hess, S.
BMC Neurology, 2005, 5:22.

CFS, Persian Gulf War Illness (PGI), and fibromyalgia (FM) are overlapping symptom complexes without objective markers or known pathophysiology. Neurological dysfunction is common. We assessed cerebrospinal fluid to find proteins that were differentially expressed in this CFS-spectrum of illnesses compared to control subjects.
Cerebrospinal fluid specimens from 10 CFS (CDC ’94 criteria), 10 PGI, and 10 control subjects (50 μl/subject) were pooled into one sample per group (cohort 1). Cohort 2 of 12 control and 9 CFS subjects had their fluids (200 μl/subject) assessed individually. After trypsin digestion, peptides were analysed by capillary chromatography, quadruple-time-of-flight mass spectrometry, peptide sequencing, bioinformatic protein identification, and statistical analysis.

Pooled CFS and PGI samples shared 20 proteins that were not detectable in the pooled control sample (cohort 1 CFS-related proteome). Multilogistic regression analysis (GLM) of cohort 2 detected 10 proteins that were shared by CFS individuals and the cohort 1 CFS-related proteome, but were not detected in control samples. Detection of >1 of a select set of 5 CFS-related proteins predicted CFS status with 80% concordance (logistic model).

The proteins were α-1-macroglobulin, amyloid precursor-like protein 1, keratin 16, orosomucoid 2 and pigment epithelium-derived factor. Overall, 62 of 115 proteins were newly described.

This pilot study detected an identical set of central nervous system, innate immune and amyloidogenic proteins in cerebrospinal fluids from two independent cohorts of subjects with overlapping CFS, PGI and FM. Although syndrome names and definitions were different, the proteome and presumed pathological mechanism(s) may be shared.

This may also excite the Amyloid fanboys and girls!

Found at: http://www.ncf-net.org/forum/amyloids.htm

Why are amyloids of potential significance to CFS patients?

The AL amyloid usually occurs secondary to multiple myeloma, or B-cell type malignancies, as well as other plasma cell dyscrasias. The AL amyloid is usually due to the deposition of the variable region of immunoglobulin light chains, either lambda or kappa chain, but the entire light chain may also be present. This description is particularly intriguing and of significance to patients with chronic fatigue syndrome due to an early medical observation made by Dr. Paul Cheney and Dr. Daniel Peterson in Lake Tahoe patients. As reported in Osler's Web in 1985, Drs. Cheney and Peterson used a then new medical test for spotting lymphomas at a presymptomatic stage. They utilized a test, developed by Harvard scientists, to monitor the progression of B-cell lymphomas since various uncommon tumors had been spotted in some of their CFS patients. The uniqueness of the test was that the measurements are done on a single-cell basis or a per-cell basis thus enabling scientists to detect very small numbers of circulating abnormal cells. The test that Drs. Cheney and Peterson utilized is known as the kappa-lambda light chain or clonal excess assay. It uses flow cytometry to quantitate cell abnormalities. It is a test that is commonly used now by oncologists for suspicions of multiple myeloma. What Drs. Cheney and Peterson learned was that 25% of their CFS patients tested positive for light chain clonal excess.

Since that time period, the NCF has found that many of our own CFS patients have tested positive for this assay as well and we believe that an important relationship exists regarding an amyloidosis. In a previous Forum, the NCF pointed out the fact that in September 2003 the CDC announced their finding of an amyloid in CFS patients although they have yet to classify it. As you may recall, last summer the NCF provided Dr. Hokama a research grant to examine CFS samples for various amyloid proteins. The NCF has recently been informed that a manuscript has been submitted by Dr. Hokama and his team and we are anxiously awaiting formal publication of their data regarding their findings on their preliminary amyloid research!

Why is all of this important to CFS patients?

Amyloid deposition is generally an irreversible pathologic process. In most instances, the constant accumulation of amyloid fibril proteins leads to progressive organ dysfunction and eventual death. This is why the NCF had funded research into amyloids and why we subsequently requested patient tissue samples.

The diagnosis of amyloid deposition is almost exclusively done by the morphologic examination of tissue material taken from biopsy samples or autopsied organs. Positive staining with a special dye and exhibition of green birefringence in polarized light are generally accepted principles, which suggest the deposition of amyloid in the examined sample. The finding of fibrils by electron microscopy in biopsies or tissues under examination confirms the diagnosis of amyloidosis. Ongoing research has revealed that different proteins can be deposited as amyloid fibrils. Approximately 20 different proteins have been discovered as constituents of amyloid so far. It is of decisive importance for the prognosis and therapy of amyloid related diseases to discover the very nature of the proteins in the deposits.

The National CFIDS Foundation has demonstrated that it is fully committed to understanding the underlying pathologic process involved in this disease. It is through your continued financial support that appropriate research be funded to resolve these important medical issues.

References:

Mechanisms of Disease: Molecular Mechanisms of Amyloidosis; Merlini GM, Bellotti V;
NEJM 349 (6): 583-596; 2003

Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic; Johnson H;
Crown Publishers, 1996

Lastly, non CFS specific - but possibly linked:

15% of persons in one small study with Parvovirus had increased serum Amyloid.
NB: Parvovirus is one virus associated with CFS

Chronic Fatigue Syndrome and Arthralgia Following Parvovirus B19 Infection
Kerr et al, 2002
Journal of Rheumatology
Source: http://www.cfsrf.com/pdf/j-rh.pdf

 

[natasa778]

methinks this has something to do with amyloids and calcium accumulation, and vice versa - excessive cellular calcium leading to amyloid production...

compare these:

"... this is the first direct observation of a connection between amyloid plaques, calcium accumulation..." http://www.mgh.harvard.edu/about/pressrelease.aspx?id=1032


and

Calcium May Predict Prostate Cancer Mortality http://www.renalandurologynews.com/calcium-may-predict-prostate-cancer-mortality/article/127527/


“…These results support the hypothesis that high serum calcium, or a factor strongly associated with it, such as high serum parathyroid hormone, increases the risk for fatal prostate cancer.
…
He added, "Both calcium and parathyroid hormone are known to promote the growth of prostate cancer cells in the laboratory… "
http://www.sciencedaily.com/releases/2008/09/080903073012.htm

confirmed just now by a Chinese study
http://www.webmd.com/prostate-cancer/news/20080903/calcium-levels-predict-prostate-cancer

 

[DysautonomiaXMRV]

Great work, thank you.

Would this tie in with the 'Channelopathy' theory of ME?
(Calcium and potassium ion channels)

From memory, intra-cellular Calcium is raised in CFS.

You mentioned amalyoid plaques and I saw an ME conference once on DVD that mentioned the theoretical risk of developing such things (Amyloid plaques) in the brain - when having ME.

A knowledgeable person on this matter in ME, is Dr Abhijit Chaudhuri, who works (interestingly) not with the National ME Centre (who pursue a psychosomatic rehabilitation programme for 'fatigue' syndrome), but at the same Hospital at Queens - in Romford, Essex. (He's a consultant neurologist who has a keen interest in the neurology of ME, and even has performed autopsies on ME brains).

From memory Dr Peter Behan was also interested in Channelopathies in ME (re: Calcium) and wrote a few research papers.

 

[lansbergen]

Host-pathogen interactions: Prions & retroviruses (p. Leblanc)

http://hvd.ens-lyon.fr/human_virolo...ion-protein-retrovirus-interactions-p-leblanc

LaboRetro
HOST-PATHOGEN INTERACTIONS: PRIONS & RETROVIRUSES (P. LEBLANC)

Pascal Leblanc Pascal Leblanc
Email: Pascal.Leblanc[at]ens-lyon.fr
Tel: +33 (0)4 72 72 86 25
Fax: +33 (0)4 72 72 81 37

Background

The cellular prion protein (PrPC) is a GPI-anchored protein expressed in almost all tissues and especially in cells belonging to the central nervous and the immune systems. PrPC is found associated with Detergent Resistant Microdomains (DRMs/rafts) at the plasma membrane, in caveolar structures and in intracellular compartments of endosomal origin (late endosomes/multivesicular bodies ie MVBs). PrPC is an essential factor for susceptibility to Transmissible Spongiform Encephalopathy (TSE), a neurodegenerative disease affecting humans and animals. TSEs are associated in most cases with the accumulation in the central nervous system of PrPSc, a partially protease-resistant isoform of the cellular prion protein PrPC. PrPSc is thought to be the causative agent of TSEs. However, none of the recent reports provided conclusive evidence that the infectious agent was composed entirely of PrPSc. Interestingly, different studies suggested that PrPSc could correspond to a by-product of a viral infection. Recent studies suggested that RNA molecules may be essential factors involved in PrPSc formation and/or in the structure of TSE agent. The seemingly contracdictory results on the nature of the TSE agent, ie PrPSc as the unique component or associated with RNAs and/or virus-like particles plead for an extensive characterization of the agent, its trafficking and the cellular mechanisms leading to its spreading in the organism.

The characterization of the cellular function of PrPC is essential to understand the role of this protein in the pathogenesis. While knockout mice did not revealed strong aberrant phenotypes, many functions of PrPC such as protection against oxidative stress, apoptosis prevention, role in immune response, cell-cell interaction or cell transduction have been identified and proposed. Recently, many studies revealed that Prion proteins can modulate the replication cycle of different viruses and especially retroviruses such as HIV-1 and murine endogenous retroviruses.

Research area

In this group, we are interested in two aspects of the prion field. The first one is a better characterization of the agent, its composition and the cellular mechanisms by which it is disseminated through the organism. The second one is the understanding of relationships between prion proteins and retroviruses and especially Human Immunodeficiency Virus type 1 (HIV-1 ; see Box1). Our objective is to characterize the interactions between prions and retroviruses (HIV-1, endogenous retroviruses) and to determine the molecular and cellular mechanisms involved in these interactions using normal and scrapie infected cellular models.

Our laboratory INSERM U758 is integrated into an ideal scientific environment at the Ecole Normale Suprieure de Lyon in the IFR128 Bioscience and displays all the facilities to work on such pathogens (L3 laboratory) and an efficient technical platform (http://www.ifr128.prd.fr).

Members of the project:

* Pascal Leblanc: Charg de recherche CR1 CNRS
* Sandrine Alais: Ingnieur dtude INSERM

Recent publications
* Alais S, Simoes S, Baas D, Lehmann S, Raposo G, Darlix JL, Leblanc P. (2008) Mouse neuroblastoma cells release prion infectivity associated with exosomal vesicles. Biol Cell. In press. [PDF] [PubMed]
* Leblanc P, Alais S, Porto-Carreiro I, Lehmann S, Grassi J, Raposo G, Darlix JL. (2006) Retrovirus infection strongly enhances scrapie infectivity release in cell culture. EMBO J. 25(12):2674-85. [Abstract] [Full Text] [PDF] [PubMed]
* Leblanc P, Baas D, Darlix JL. (2004) Analysis of the interactions between HIV-1 and the cellular prion protein in a human cell line. J Mol Biol. 337(4):1035-51. [Full Text] [PDF] [PubMed]

 

[lansbergen]

Prion clearance

http://vir.sgmjournals.org/cgi/content/abstract/86/10/2913

J Gen Virol 86 (2005), 2913-2923; DOI 10.1099/vir.0.80947-0

2005 Society for General Microbiology

Prion clearance in bigenic mice

Jiri G. Safar1,2, Stephen J. DeArmond1,3, Katarzyna Kociuba1, Camille Deering1, Svetlana Didorenko1, Essia Bouzamondo-Bernstein3, Stanley B. Prusiner1,2,4 and Patrick Tremblay1,2,{dagger}

1 Institute for Neurodegenerative Diseases, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA
2 Department of Neurology, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA
3 Department of Pathology, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA
4 Department of Biochemistry and Biophysics, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA

The clearance of prions from the brain was investigated in bigenic mice designated Tg(tTA : PrP+/0)3, in which expression of the cellular prion protein (PrPC) was regulated by oral doxycycline administration. With suppression of PrPC expression, the incubation time for RML prions was prolonged almost threefold from ~150 to ~430 days. To determine the clearance rate of disease-causing PrPSc, bigenic mice were given oral doxycycline beginning 98 days after inoculation with RML prions and sacrificed at various time points over the subsequent 56 days. The half-life (t1/2) for PrPSc was ~15 days in mouse brain, in reasonable agreement with the apparent t1/2 of 30 h that was determined in a separate study for scrapie-infected mouse neuroblastoma (ScN2a) cells in culture. Both protease-sensitive and -resistant conformers of PrPSc were cleared at the same rate. The t1/2 value for PrPC clearance from brain was ~18 h, which was considerably longer than the t1/2 of 5 h found in ScN2a cells. The capability of the brain to clear prions raises the possibility that PrPSc is normally made at low levels and continually cleared, and that PrPSc may have a function in cellular metabolism. Moreover, these bigenic mice make it possible to determine both components of PrPSc accumulation, i.e. the rates of formation and clearance, for various strains of prions exhibiting different incubation times.

Supplementary material is available in JGV Online.

 

[lansbergen]

prion clearance

http://www.ncbi.nlm.nih.gov/pubmed/17944938

FEBS J. 2007 Nov;274(22):5834-44. Epub 2007 Oct 18.

CpG and LPS can interfere negatively with prion clearance in macrophage and microglial cells.

Gilch S, Schmitz F, Aguib Y, Kehler C, Blow S, Bauer S, Kremmer E, Schtzl HM.

Institute of Virology, Prion Research Group, Technical University of Munich, Germany.
Abstract

Cells of the innate immune system play important roles in the progression of prion disease after peripheral infection. It has been found in vivo and in vitro that the expression of the cellular prion protein (PrP(c)) is up-regulated on stimulation of immune cells, also indicating the functional importance of PrP(c) in the immune system. The aim of our study was to investigate the impact of cytosine-phosphate-guanosine- and lipopolysaccharide-induced PrP(c) up-regulation on the uptake and processing of the pathological prion protein (PrP(Sc)) in phagocytic innate immune cells. For this purpose, we challenged the macrophage cell line J774, the microglial cell line BV-2 and primary bone marrow-derived macrophages in a resting or stimulated state with various prion strains, and monitored the uptake and clearance of PrP(Sc). Interestingly, stimulation led either to a transient increase in the level of PrP(Sc) relative to unstimulated cells or to a decelerated degradation of PrP(Sc). These features were dependent on cell type and prion strain. Our data indicate that the stimulation of innate immune cells may be able to support transient prion propagation, possibly explained by an increased PrP(c) cell surface expression in stimulated cells. We suggest that stimulation of innate immune cells can lead to an imbalance between the propagation and degradation of PrP(Sc).

PMID: 17944938 [PubMed - indexed for MEDLINE]

 

[ixchelkali]

Good, I'm glad they're starting to do this kind of study.

 

[lansbergen]

PrP, ALS, and Autism Spectrum Disorders

http://www.prionetcanada.ca/detail....e=16.+PrP,+ALS,+and+Autism+Spectrum+Disorders


13. PrP, ALS, and Autism Spectrum Disorders

Principal Investigator: David Westaway, University of Alberta

Co-investigator:
Jack Jhamandas, University of Alberta

Project Description:
This project proposes to link prion protein biochemistry to Amyotrophic Lateral Sclerosis (ALS) and/or autism by first creating changes in the expression of the various forms of a membrane protein called DPP6 and then performing an array of phenotypic analyses on laboratory mice.

(High-Impact 2009)

related links:
Project website

Last Updated: 5/3/2010 5:48:46 PM

 

[jimbob]

Good catch georgie girl, you're always on top of things! I had better be careful with my unit if this is the case! LOL

 

[lansbergen]

Lithium induces clearance of protease resistant prion protein in prion-infected cells

http://www.ncbi.nlm.nih.gov/pubmed/19183256

J Neurochem. 2009 Apr;109(1):25-34. Epub 2009 Feb 20.

Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy.

Heiseke A, Aguib Y, Riemer C, Baier M, Schtzl HM.

Institute of Virology, Technische Universitt Mnchen, Munich, Germany.

Abstract

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(Sc)) 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(Sc). Co-treatment with lithium and rapamycin, a drug widely used to induce autophagy, had an additive effect on PrP(Sc) clearance compared to treatment with either drug alone. In addition, we provide evidence that the ability to reduce PrP(Sc) 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(Sc)-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(Sc) may provide an additional mechanism for reduction of PrP(Sc) by lithium-induced autophagy.

PMID: 19183256 [PubMed - indexed for MEDLINE]

 

[lansbergen]

Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbala

http://www.ncbi.nlm.nih.gov/pubmed/...d_DefaultReportPanel.Pubmed_RVDocSumNeurochem

Res. 2004 Mar;29(3):493-504.

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.

Abstract

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.

 

[lansbergen]

The peculiar interaction between mammalian prion protein and RNA

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634520/

Prion. 2008 AprJun; 2(2): 6466.

PMCID: PMC2634520
Copyright 2008 Landes Bioscience

The peculiar interaction between mammalian prion protein and RNA

Mariana PB Gomes,1 Yraima Cordeiro,2 and Jerson L Silvacorresponding author1
1Programa de Biologia Estrutural; Instituto de Bioqumica Mdica
2Faculdade de Farmcia; Universidade Federal do Rio de Janeiro; Rio de Janeiro Brazil
corresponding authorCorresponding author.
Correspondence to: Jerson L. Silva; Universidade Federal do Rio de Janeiro; Instituto de Bioquimica Medica; IBqM-Centro de Ciencias da Saude Sala E-10; Rio de Janeiro RJ 21941-590 Brazil; Email: jerson@bioqmed.ufrj.br

Received July 31, 2008; Accepted September 11, 2008.

Abstract
In the past decade, the interaction between prions and nucleic acids has garnered significant attention from the scientific community. For many years, the participation of RNA and/or DNA in prion pathology has been largely ruled out by the protein-only hypothesis, but this is now being reconsidered. Experimental data now indicate that nucleic acids (particularly RNA), besides being carriers of genetic information, function as important key components during development, physiological responsiveness and cellular signaling. This revelation has brought a new perspective to prion pathology. Here we discuss the role of RNA molecules in prion protein aggregation and the resulting cellular toxicity. We combine our most recent findings with existing literature to shed new light on this exciting field of research.

 

[Rosemary]

http://www.prionetcanada.ca/detail....e=16.+PrP,+ALS,+and+Autism+Spectrum+Disorders


13. PrP, ALS, and Autism Spectrum Disorders

Principal Investigator: David Westaway, University of Alberta

Co-investigator:
Jack Jhamandas, University of Alberta

Project Description:
This project proposes to link prion protein biochemistry to Amyotrophic Lateral Sclerosis (ALS) and/or autism by first creating changes in the expression of the various forms of a membrane protein called DPP6 and then performing an array of phenotypic analyses on laboratory mice.

(High-Impact 2009)

related links:
Project website

Last Updated: 5/3/2010 5:48:46 PM

Hello lansbergen,

Thanks for posting these very interesting links !

One of the proteases that I am really interested in is Cathepsin D..

Cathepsin D is involved in the clearance of Alzheimer's beta-amyloid protein.

http://www.ncbi.nlm.nih.gov/pubmed/8914975?dopt=AbstractPlus&holding=f1000,f1000m,isrctn

and Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects.

http://www.ncbi.nlm.nih.gov/pubmed/...ed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=14

 

[Rosemary]

Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subj

http://www.ncbi.nlm.nih.gov/pubmed/...ed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=14

Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects.
Sheikh AM, Li X, Wen G, Tauqeer Z, Brown WT, Malik M.

Department of Neurochemistry, NY State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY 10314, USA.

Abstract
Autism is a severe neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior. Recent studies suggest that apoptotic mechanisms may partially contribute to the pathogenesis of this disorder. Cathepsin D is the predominant lysosomal protease and is abundantly expressed in the brain. It plays an important role in regulation of cellular apoptosis and has been shown to mediate apoptosis induced by cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. In this study, we examined the expression levels of cathepsin D in the autistic brain. We found that cathepsin D protein expression was significantly increased in the frontal cortex, in pyramidal and granule cells of the hippocampus, and in cerebellar neurons in autistic subjects as compared to controls. In addition, we found that the expression of the anti-apoptotic protein Bcl-2 was significantly decreased, while caspase-3, a critical executioner of apoptosis, was increased in the cerebellum of autistic subjects. Previously our studies have shown that Bcl-2 expression is decreased and the BDNF-Akt-Bcl-2 pathway is compromised in the frontal cortex of autistic subjects, which suggested that increased apoptosis may be involved in the pathogenesis of autism. Our current finding of decreased Bcl-2 and increased capase-3 in the cerebellum of autistic subjects further supports this suggestion. In addition, the finding of increased cathepsin D in the cerebellum of autistic subjects suggests that, through its regulation of apoptosis, the altered activities of cathepsin D in the autistic brain may play an important role in the pathogenesis of autism.

 

[lansbergen]

Prostatic acid phosphatase in breast cyst fluid.

http://www.ncbi.nlm.nih.gov/pubmed/19108401

Malays J Pathol. 2007 Dec;29(2):95-9.

Prostatic acid phosphatase in breast cyst fluid.

Erbas H, Erten O, Irfanoglu ME.

Department of Biochemistry, Faculty of Medicine, University of Trakya, Edirne, Turkey. herbas@mail.trakya.edu.tr

Abstract

Prostatic Acid Phosphatase (PAP) is mostly found in the epithelial cells and secretions of the prostate gland. It has also been found to be present in several tissues and biological fluid. Gross cystic breast disease is the commonest benign breast condition and several studies have shown that women with palpable breast cysts may have a higher risk of developing breast cancer. There are two types of breast cyst and women with apocrine breast cyst may have a higher risk of developing breast cancer than women with breast cysts lined by flattened epithelium. The growth inhibitory effect of transforming growth factor beta (TGF-beta) on epithelial cells suggests a potential protective role in breast cancer. TGF-beta is secreted as a high molecular weight complex in a biologically inactive or latent form and activation of TGF-beta is necessary for the exertion of its effects on target cells. Prostate specific antigen (PSA) has been found in breast cyst fluid (BCF) and it may have a protective effect on the development of several carcinomas by activating TGF-beta. As a similar molecule to PSA, PAP may also involve in this mechanism. We investigated the presence of PAP in two groups of BCF using an ELISA kit. PAP was found to be present in BCF but there was not a statistically significant difference between the two cyst groups. The presence of PAP in BCF may suggest its possible role in the development of breast cancer from cystic breast diseases. A possible role of PAP on TGF-beta activation needs further investigation.

PMID: 19108401 [PubMed - indexed for MEDLINE]

 

[lansbergen]

The Female Prostate Revisited

http://www3.interscience.wiley.com/journal/118496214/abstract

Journal of Sexual Medicine Volume 4 Issue 5, Pages 1388 - 1393

Published Online: 18 Jul 2007

Published on behalf of International Society for Sexual Medicine

The Female Prostate Revisited: Perineal Ultrasound and Biochemical Studies of Female Ejaculate

Florian Wimpissinger, MD, FEBU,* Karl Stifter, PhD, Wolfgang Grin, MD, and Walter Stackl, MD *
*Department of Urology, Rudolfstiftung HospitalUrology, Vienna, Austria; Institute for Perineometry and Sextherapy, Vienna, Austria; Rudolfstiftung HospitalObstetrics and Gynecology, Vienna, Austria
Correspondence to Florian Wimpissinger; Rudolfstiftung HospitalUrology, Juchgasse 25 Vienna A1030, Austria. Tel: +431711654808; Fax: +431711654809; E-mail: florian.wimpissinger@gmx.at

Copyright 2007 International Society for Sexual Medicine

Introduction. Many speculations have been made on the possible existence of a "female prostate gland" and "female ejaculation." Despite several reports on the subject, controversy still exists around the "female prostate" and whether such a gland might be the source of fluid emitted during orgasm (ejaculation).

Aim. To investigate the ultrasonographic, biochemical, and endoscopic features in two women who reported actual ejaculations during orgasm.

Main Outcome Measures. Perineal ultrasound studies, as well as biochemical characteristics of ejaculate and urethroscopy, have been performed in two women.

Methods. Two premenopausal women44 and 45 years of agewho actually reported fluid expulsion (ejaculation) during orgasm have been investigated. Ultrasound imaging, biochemical studies of the ejaculated fluid, and endoscopy of the urethra have been used to identify a prostate in the female. Ejaculated fluid parameters have been compared to voided urine samples.

Results. On high-definition perineal ultrasound images, a structure was identified consistent with the gland tissue surrounding the entire length of the female urethra. On urethroscopy, one midline opening (duct) was seen just inside the external meatus in the six-o'clock position. Biochemically, the fluid emitted during orgasm showed all the parameters found in prostate plasma in contrast to the values measured in voided urine.

Conclusions. Data of the two women presented further underline the concept of the female prostate both as an organ itself and as the source of female ejaculation. Wimpissinger F, Stifter K, Grin W, and Stackl W. The female prostate revisited: Perineal ultrasound and biochemical studies of female ejaculate. J Sex Med 2007;4:13881393.

 

[lansbergen]

Steroid-Involved Transcriptional Regulation of Human Genes Encoding PAP

Endocrinology Vol. 138, No. 9 3764-3770 Copyright 1997 by The Endocrine Society

http://endo.endojournals.org/cgi/content/full/138/9/3764

Steroid-Involved Transcriptional Regulation of Human Genes Encoding Prostatic Acid Phosphatase, Prostate-Specific Antigen, and Prostate-Specific Glandular Kallikrein1

Jing-Dong Shan, Katja Porvari, Minna Ruokonen, Auli Karhu, Virpi Launonen, Pirjo Hedberg, Jouko Oikarinen and Pirkko Vihko

Biocenter Oulu, World Health Organization Collaborating Center for Research in Human Reproduction and Department of Clinical Chemistry, University of Oulu, Oulu, Finland
Address all correspondence and requests for reprints to: Dr. Katja Porvari, Kajaanintie 50, FIN-90220 Oulu, Finland. E-mail: kporvari@whoccr.oulu.fi.

Abstract

We have compared the steroid regulation of human genes encoding prostatic acid phosphatase (hPAP), prostate-specific antigen (hPSA), and prostate-specific glandular kallikrein (hK2) at the level of transcription. Reporter constructs of hPAP promoter covering the region -734/+467 were functional in both prostatic (LNCaP and PC-3) and nonprostatic (CV-1) cell lines in transient transfections. hPAP -231/+50 with eight identified transcription factor-binding sites showed the highest, and hPAP -734/+467 showed the lowest transcriptional activity in CV-1 cells. The hPAP promoter could not be induced with androgen, glucocorticoid, or progesterone, contrary to the hPSA (-620/+40) and hK2 (-493/+27) promoters in PC-3 cells cotransfected with the respective steroid receptor expression vector. Therefore, steroids cannot directly regulate hPAP gene expression via receptor binding to steroid response elements at -178 and +336, which have been shown to have androgen receptor-binding ability in vitro. Glucocorticoid was the most powerful activator of the hPSA construct at 10-nM steroid concentrations. On the contrary, glucocorticoid stimulation of the transcriptional activity of the hK2 construct was the weakest among the tested steroids. The results indicate that the steroid response elements in the proximal promoters of hPSA and hK2 genes are not androgen specific, offering the molecular basis for the expression of these genes outside the prostate in tissues containing steroid receptors.