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Biomedical subjects

P Friedrich

Publications and source records attributed to P Friedrich.

At least 19 recordsLinked to original sources
PubMed2006

Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease.

In addition to senile plaques, neurofibrillary tangles are characteristic of Alzheimer's disease (AD) pathology, suggesting a clear involvement of the microtubule-associated protein tau (MAPT) in AD. Recent findings, suggesting that the H1c haplotype is associated with increased risk, now also implicate MAPT genetically. In this study, we aim to clarify this association by a fine mapping approach using both a traditional phenotypic association analysis and a quantitative trait (QT) analysis using cerebrospinal fluid (CSF) tau protein levels in the German population. Here, we report that both methodologies identify that the H1c haplotype may play important role in AD (AD risk, P=0.007, uncorrected; CSF tau levels, P=0.027, uncorrected). Further, the use of a sliding window approach in the QT analysis allowed for the narrowing down of the region where a probable causal variant may be located. The data suggest that this may lie at or within close proximity to the rs242557 single nucleotide polymorphism as association with CSF tau levels seems to be primarily driven by rs242557 in a gene dosage-dependent manner (trend model: P=0.002, uncorrected). These findings provide functional evidence to support the genetic association of MAPT with AD.

Aged↗
PubMed2006

No association of vacuolar protein sorting 26 polymorphisms with Alzheimer's disease.

Using a case-control sample we evaluated a possible involvement of the Vacuolar protein sorting 26 (VPS26) gene in the pathogenesis of AD. VPS26 located at 10q22.1 denotes a retromer subunit functionally involved in the cellular trafficking of Memapsin 2 (BACE). Genotyping of eight single nucleotide polymorphisms covering the complete VPS26 gene and haplotypic analysis revealed no association with AD. Thus, we conclude that VPS26 can be excluded as a major positional and functional candidate gene conferring risk to AD.

Aged↗
PubMed2005

First results from the CERN axion solar telescope.

Hypothetical axionlike particles with a two-photon interaction would be produced in the sun by the Primakoff process. In a laboratory magnetic field ("axion helioscope"), they would be transformed into x-rays with energies of a few keV. Using a decommissioned Large Hadron Collider test magnet, the CERN Axion Solar Telescope ran for about 6 months during 2003. The first results from the analysis of these data are presented here. No signal above background was observed, implying an upper limit to the axion-photon coupling g(agamma)<1.16x10(-10) GeV-1 at 95% C.L. for m(a) less, similar 0.02 eV. This limit, assumption-free, is comparable to the limit from stellar energy-loss arguments and considerably more restrictive than any previous experiment over a broad range of axion masses.

Journal Article↗
PubMed2005

Enhancement of synaptic strength in the somatosensory cortex following nerve injury does not parallel behavioural alterations.

Following infraorbital nerve transection, underlying mechanisms of the altered synaptic strength were studied in rat barrel cortex slice experiments. In addition to the in vitro electrophysiological studies, open-field tests were run to detect possible behavioural changes associated with cortical oversensitization. Enhanced NMDA receptor-mediated component of the evoked field response appeared in the barrel cortex after nerve injury. The alteration was transient, very distinct on the first day following injury, and almost returned to normal level by the end of the second week. Behavioural changes had not followed this time-course since long-lasting alterations were detected in the open-field test. These observations are in agreement with findings that showed biphasic regenerative processes following nerve injuries in other cortical areas.

2-Amino-5-phosphonovalerate↗
PubMed2002

The phosphorylation state of threonine-220, a uniquely phosphatase-sensitive protein kinase A site in microtubule-associated protein MAP2c, regulates microtubule binding and stability.

Phosphorylation of microtubule-associated protein 2 (MAP2) has a profound effect on microtubule stability and organization. In this work a consensus protein kinase A (PKA) phosphorylation site, T(220), of juvenile MAP2c is characterized. As confirmed by mass spectrometry, this site can be phosphorylated by PKA but shows less than average reactivity among the 3.5 +/- 0.5 phosphate residues incorporated into the protein. In contrast, T(220) is uniquely sensitive to dephosphorylation: three major Ser/Thr protein phosphatases, in the order of efficiency PP2B > PP2A(c) > PP1(c), remove this phosphate group first. MAP2c specifically dephosphorylated at this site binds and stabilizes microtubules stronger than either fully phosphorylated or nonphosphorylated MAP2c. Phosphorylation of this site also affects proteolytic sensitivity of MAP2c, which might represent a further level of control in this system. Thus, the phosphorylation state of T(220) may be a primary determinant of microtubule function.

Amino Acid Sequence↗
PubMed2001

Domain III of calpain is a ca2+-regulated phospholipid-binding domain.

The X-ray structure of m-calpain shows that domain III of the large subunit is structurally related to C2 domains, Ca2+-regulated lipid binding modules in many enzymes. To address whether this structural similarity entails functional analogy, we have characterized recombinant domain III from rat micro- and m-calpain and Drosophila CALPB. In a Ca2+ overlay assay domain III displays a large capacity for Ca2+ binding, commensurable with that of domain IV, the principal Ca2+-binding domain of calpains. The amount of Ca2+ bound to domain III increases 2- to 10-fold upon the addition of liposomes containing 20-40% di- and triphosphoinositides. Conversely, phospholipid-binding in spin-column size-exclusion chromatography is significantly promoted by Ca2+, in a manner similar to known C2 domains. These results suggest that domain III might be the primary lipid binding site of calpain and may play a decisive role in orchestrating Ca2+- and lipid activation of the enzyme.

Amino Acid Sequence↗
PubMed2001

Frequency decoding of fast calcium oscillations by calpain.

We report the development of a novel procedure for generating fast, high-frequency Ca2+ oscillations in vitro and the frequency-dependent activation of m-calpain, the Ca2+-activated intracellular cysteine protease. The procedure is based upon liberating Ca2+ from a cage, DM-Nitrophen, by repetitive UV laser pulses and its concomitant binding by a 'slow' chelator, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetate (DOTA). It is shown that a full control over the pattern of oscillations can be readily achieved because the half-life of individual spikes is determined by DOTA concentration and pH, whereas peak amplitude can be adjusted by light intensity. Frequency is only limited by the physical parameters of the light source. The sensitivity of calpain activation to the frequency of Ca2+ oscillations was monitored by the cleavage of microtubule-associated protein 2, a very sensitive physiological substrate of the enzyme. One hundred transients at a peak Ca2+ concentration of 10 microM were presented at various pH values and frequencies ranging from 1 to 50 Hz. At pH 6.0 and 7.0 significant activation occurred at high frequencies (20 and 50 Hz), but here Ca2+ accumulated due to the overlap of transients; at low frequencies (1 and 3 Hz) where Ca2+ accumulation was negligible, there was no calpain activation. At pH 8.0, where individual transients do not overlap even at 50 Hz, frequency-dependence of activation is seen when calpain is sensitized to Ca2+ by autolysis and by the addition of a phospholipid, phosphatidylinositol-4,5-bisphosphate. Our results show that calpain is sensitive to the frequency of fast Ca2+ oscillations in vitro, which is of potential physiological significance.

Calcium↗
PubMed2000

Inhibitory effect of a brain derived peptide preparation on the Ca++-dependent protease, calpain.

Overactivated calpain might be a key factor in destruction of cytoskeletal proteins involved in the pathophysiology of ischemia and disorders like Alzheimer's disease. Therapeutic effects imply the possible interference of Cerebrolysin (Ebewe Arzneimittel, Austria) with these molecular events. In this work several in vitro methods have been applied to investigate the interaction between Cerebrolysin and calpain [Enzyme Commission (EC) number: 3.4.22.17]. A conventional caseinolytic assay beside two flourimetric assays using a synthetic peptide substrate and a fluorescence labelled cytoskeletal protein [microtubule-associated protein 2 labelled with 5-([4,6-dichlorotriazin-2-yl]amino) fluorescein (MAP2-DTAF)] respectively for a highly sensitive fluorimetric calpain activity assay were applied for kinetic analysis. The caseinolytic assay showed that the drug inhibits both mu- and m-calpain and to a significantly lower extent also trypsin [Enzyme Commission (EC) number: 3.4.21.1] and papain [Enzyme commission (EC) number: 3.4.22.6]. Dialysis experiments revealed Cerebrolysin mediated calpain inhibition to be reversible. Kinetic analysis exhibited a non-competitive, or tight-binding competitive, mode of inhibition. This latter mode, substantiated by serial dilution experiments, and the likely existence of calpastatin in a brain derivative suggests the occurrence of calpastatin fragments or calpastatin-like fragments in Cerebrolysin. The clearly competitive inhibition of trypsin by the drug indicates distinct mechanisms and active components against different proteases.

Amino Acids↗
PubMed1999

Characterization of two recombinant Drosophila calpains. CALPA and a novel homolog, CALPB.

We have sequenced the cDNA of a novel Ca(2+)-activated cysteine proteinase (calpain) from the fruit fly, Drosophila melanogaster. The predicted protein, designated as CALPB, shows high similarity to the previously identified Drosophila calpain, CALPA. The two proteins were expressed in Escherichia coli and purified to homogeneity by metal-chelate affinity chromatography either from inclusion bodies or from the bacterial cytosol. Both enzymes were Ca(2+)-dependent proteinases and attained half-maximal activation in the presence of millimolar Ca(2+). The activity and the rate of activation of CALPA, but not CALPB, could be activated by phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid. A truncated form of CALPA, lacking the CALPA-specific unique insertion region, has also been expressed and characterized. Although it lacked the 16-amino acid long putative membrane-anchoring segment, its activation by phospholipids was similar to that of the full-length CALPA protein. The enzymes undergo N-terminal autolysis in a Ca(2+)-dependent manner which was shown with CALPB to run parallel with enzyme activation. Moreover, fully autolyzed CALPB lacked the characteristic activation phase indicating the requirement for autolysis upon activation of this calpain form in vitro. The analysis of the mechanism of activation in Drosophila calpains seems to corroborate the autolysis model of calpain activation.

Amino Acid Sequence↗
PubMed1999

The evolution of the calpain family as reflected in paralogous chromosome regions.

Calpains, the Ca(2+)-dependent intracellular proteinases, are involved in the regulation of distinct cellular pathways including signal transduction and processing, cytoskeleton dynamics, and muscle homeostasis. To investigate the evolutionary origin of diverse calpain subfamilies, a phylogenetic study was carried out. The topology of the calpain phylogenetic tree has shown that some of the gene duplications occurred before the divergence of the protostome and deuterostome lineages. Other gene doublings, leading to vertebrate-specific calpain forms, took place during early chordate evolution and coincided with genome duplications as disclosed by the localization of calpain genes to paralogous chromosome regions in the human genome. On the basis of the phylogenetic tree, the time of gene duplications, and the localization of calpain genes, we propose a model of tandem and chromosome duplications for the evolution of vertebrate-specific calpain forms. The data presented here are consistent with scenarios proposed for the evolution of other multigene families.

Amino Acid Sequence↗
PubMed1999

[Letrozole (Femara), a new aromatase inhibitor for advanced breast cancer].

The study compares letrozole (Femara and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with anti-estrogens. 555 women were randomly assigned letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an open-label, multicenter trial. The primary end-point was objective response rate (ORR), with time events as secondary. ORR was analysed nine months after enrollment of the last patient, while survival was analysed 15 months after the last patients was enrolled. We report the results of these analyses plus an extended period of observation (covering a total duration of approximately 45 months) to determine the duration of response and clinical benefit. Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of response and stable disease was longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to progression, time to treatment failure and overall survival. Treatment-related adverse events occurred in fewer patients on letrozole (33%) than on AG (46%). Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-estrogens.

Aged↗
PubMed1998

Synaptic metaplasticity and the local charge effect in postsynaptic densities.

Synaptic plasticity might be one of the elementary processes that underlies higher brain functions, such as learning and memory. Intriguingly, the capacity of a synapse for plastic changes itself displays marked variation or plasticity. This higher-order plasticity, or metaplasticity, appears to depend on the same macromolecules as plasticity, most notably the NMDA receptor and Ca2+/calmodulin kinase II; yet we do not understand metaplasticity in molecular terms. Metaplasticity has a feedback-inhibition character that confers stability to synaptic patterns, whereas in plasticity, the molecular events implicated tend to have an opposite effect. As a resolution to this difference, we suggest that metaplasticity be considered in a biophysical context. It has been shown that autophosphorylation of Ca2+/calmodulin kinase II in postsynaptic densities generates changes in the local electrostatic potential sufficient to affect the direction of synaptic plasticity. We propose that this finding could help explain both the puzzling abundance of Ca2+/calmodulin kinase II in the postsynaptic density and the metaplasticity of synaptic transmission.

Calcium-Calmodulin-Dependent Protein Kinase Type 2↗
PubMed1998

Prion proteins as memory molecules: an hypothesis.

Prions are infectious agents widely implicated in a variety of mammalian neurodegenerative diseases generally referred to as transmissible spongiform encephalopathies. Their infectivity is primarily associated with an aberrant conformation of a host-encoded protein, the prion protein, induced by the prion itself in an autocatalytic reaction. The physiological function of this protein is not known. In this paper we suggest that alternative conformations of the prion protein, other than its pathological scrapie state, exist and that the self-sustaining autocatalytic propagation of these states underlies its normal cellular function. In kinetic model calculations we show that the prion protein may constitute a bi-stable molecular switch that can structurally encode and stably store information. A number of cases of prion involvement in normal cellular function and ample molecular detail of pathological prion propagation are cited and correlated to substantiate the implications of this tenet. Our contention is that the prion hypothesis should be extended to a wide variety of physiological processes. We propose that prion proteins are stable determinants of phenotype, operating in diverse functions possibly including memory.

Animals↗
PubMed1998

TER94, a Drosophila homolog of the membrane fusion protein CDC48/p97, is accumulated in nonproliferating cells: in the reproductive organs and in the brain of the imago.

We have cloned a Drosophila homolog of the membrane fusion protein CDC48/p97. The open reading frame of the Drosophila homolog encodes an 801 amino acid long protein (TER94), which shows high similarity to the known CDC48/p97 sequences. The chromosomal position of TER94 is 46 C/D. TER94 is expressed in embryo, in pupae and in imago, but is suppressed in larva. In the imago, the immunoreactivity was exclusively present in the head and in the gonads of both sexes. In the head the most striking staining was observed in the entire neuropil of the mushroom body and in the antennal glomeruli. Besides TER94, sex-specific forms were also detected in the gonads of the imago: p47 in the ovaries and p98 in the testis. TER94/p47 staining was observed in the nurse cells and often in the oöcytes, while TER94/p98 staining was present in the sperm bundles. On the basis of its distribution we suggest that TER94 functions in the protein transport utilizing endoplasmic reticulum and Golgi derived vesicles.

Animals↗
PubMed1998

Mycobacterium bovis in coyotes from Michigan.

During a survey for tuberculosis in wild carnivores and omnivores, Mycobacterium bovis was cultured from pooled lymph nodes of three adult female coyotes (Canis latrans) harvested by hunters in Michigan (USA). No gross or histologic lesions suggestive of tuberculosis were seen in these animals. One coyote was taken from Montmorency county and two coyotes from Alcona county located in the north-eastern portion of Michigan's Lower Peninsula where free-ranging white-tailed deer (Odocoileus virginianus) have been found infected with bovine tuberculosis. It is thought that these coyotes became infected with M. bovis through the consumption of tuberculous deer. Other species included in the survey were the opossum (Didelphis virginiana), raccoon (Procyon lotor), red fox (Vulpes vulpes), bobcat (Felis rufus), and badger (Taxidea taxus).

Animal Feed↗