TY  - JOUR
A1  - Enssle, Jörg
A1  - Weylandt, Karsten-Henrich
T1  - Secure and optimized detection of PNPLA3 rs738409 genotype by an improved PCR-restriction fragment length polymorphism method
JF  - BioTechniques : the international journal of life science methods
N2  - The PNPLA3 reference single-nucleotide polymorphism rs738409 has been identified as a predisposing factor for nonalcoholic fatty liver disease. A simple method based on PCR and restriction fragment length polymorphism (RFLP) analysis had been published to detect the nonpathogenic allele PNPLA3 rs738409 variant. The presence of the pathogenic variant was deduced by the indigestibility of the corresponding PCR product with BtsCI recognizing the nonpathogenic allele. However, one cannot exclude that an enzymatic reaction does not occur for other, more trivial, reasons. For safe and secure detection of the pathogenic PNPLA3 rs738409, we have further developed the PCR-restriction fragment length polymorphism method by adding a second restriction enzyme digest, clearly identifying the correct PNPLA3 alleles and in particular the pathogenic variant. <br /> METHOD SUMMARY <br /> The method presented here represents an improved genetic diagnosis of the PNPLA3 rs738409 alleles based on conventional and inexpensive molecular biological methods. We used methodology based on PCR and restriction fragment length polymorphisms and clearly identified both described alleles by the use of two restriction enzymes. Digestion of individuals' specific PNPLA3 PCR fragments with both enzymes in independent reactions clearly showed the PNPLA3 rs738409 genotype.
KW  - n-3 polyunsaturated fatty acid therapies
KW  - nonalcoholic fatty liver
KW  - disease
KW  - PCR– RFLP
KW  - PNPLA3
KW  - rs738409
Y1  - 2021
U6  - https://doi.org/10.2144/btn-2020-0163
SN  - 0736-6205
SN  - 1940-9818
VL  - 70
IS  - 6
SP  - 345
EP  - 349
PB  - Future Science Ltd.
CY  - London
ER  - 
TY  - JOUR
A1  - Li, Chen
A1  - Stoma, Svetlana
A1  - Lotta, Luca A.
A1  - Warner, Sophie
A1  - Albrecht, Eva
A1  - Allione, Alessandra
A1  - Arp, Pascal P.
A1  - Broer, Linda
A1  - Buxton, Jessica L.
A1  - Boeing, Heiner
A1  - Langenberg, Claudia
A1  - Codd, Veryan
T1  - Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length
JF  - American Journal of Human Genetics
N2  - Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
KW  - Mendelian randomization
KW  - risk
KW  - variants
KW  - disease
KW  - cancer
KW  - loci
KW  - database
KW  - genes
KW  - heart
KW  - gwas
Y1  - 2019
VL  - 106
IS  - 3
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - GEN
A1  - Li, Chen
A1  - Stoma, Svetlana
A1  - Lotta, Luca A.
A1  - Warner, Sophie
A1  - Albrecht, Eva
A1  - Allione, Alessandra
A1  - Arp, Pascal P.
A1  - Broer, Linda
A1  - Buxton, Jessica L.
A1  - Boeing, Heiner
A1  - Langenberg, Claudia
A1  - Codd, Veryan
T1  - Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1205 
KW  - Mendelian randomization
KW  - risk
KW  - variants
KW  - disease
KW  - cancer
KW  - loci
KW  - database
KW  - genes
KW  - heart
KW  - gwas
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-526843
SN  - 1866-8372
IS  - 3
ER  - 
TY  - THES
A1  - Gibert, Arthur
T1  - Influence of Amyloid Aggregates on the Trafficking and Signaling of GPCRs
T1  - Einfluss von Amyloidaggregaten auf den Transport und die Signalübertragung von G-Protein-gekoppelten Rezeptoren
N2  - The prevalence of diseases associated with misfolded proteins increases with age. When cellular defense mechanisms become limited, misfolded proteins form aggregates and may also develop more stable cross-β structures ultimately forming amyloid aggregates. Amyloid aggregates are associated with neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease. The formation of amyloid deposits, their toxicity and cellular defense mechanisms have been intensively studied. However, surprisingly little is known about the effects of protein aggregates on cellular signal transduction. It is also not understood whether the presence of aggregation-prone, but still soluble proteins affect signal transduction. 
In this study, the still soluble aggregation-prone HttExon1Q74 and its amyloid aggregates were used to analyze the effect of amyloid aggregates on internalization and receptor activation of G protein-coupled receptors (GPCRs), the largest protein family of mammalian cell surface receptors involved in signal transduction. The aggregated HttExon1Q74, but not its soluble form, could inhibit ligand-induced clathrin-mediated endocytosis (CME) of various GPCRs. Most likely this inhibitory effect is based on a terminal sequestration of the HSC70 chaperone to the aggregates which is necessary for CME. Using the vasopressinV1a receptor (V1aR) and the corticotropin-releasing factor receptor 1 (CRF1R) as a model, it could be shown that the presence of HttExon1Q74 aggregates and the inhibition of ligand-induced CME leads to an accumulation of desensitized receptors at the plasma membrane. In turn, this disrupts Gq-mediated Ca2+ signaling and Gs-mediated cAMP signaling of the V1aR and the CRF1R respectively. In contrast to HttExon1Q74 amyloid aggregates, soluble HttExon1Q74 as well as amorphous aggregates did not inhibit GPCR internalization and signaling demonstrating that cellular signal transduction mechanisms are specifically impaired in response to the formation of amyloid aggregates.
In addition, preliminary experiments could show that HttExon1Q74 aggregates provoke an increase in membrane expression of a protein from a structurally and functionally unrelated membrane protein family, namely the serotonin transporter SERT. As SERT is the main pharmacological target to treat depression this could shed light on this commonly occurring comorbidity in neurodegenerative diseases, in particular in early disease states.
N2  - Die Prävalenz von Krankheiten, die mit fehlgefalteten Proteinen assoziiert sind, nimmt mit dem Alter zu. Wenn die zellulären Abwehrmechanismen weniger effizient werden, können fehlgefaltete Proteine nicht nur einfache Aggregate bilden, sondern auch stabilere Cross-β-Strukturen, die am Ende zu sogenannten Amyloidaggregaten führen können. Amyloidaggregate sind mit neurodegenerativen Erkrankungen wie z. B. der Alzheimer Erkrankung und dem Huntington-Syndrom assoziiert. Die Bildung von Amyloidablagerungen, ihre Toxizität und die zellulären Abwehrmechanismen wurden in den letzten Jahren intensiv untersucht. Über die Auswirkungen von Proteinaggregaten auf die zelluläre Signaltransduktion ist jedoch überraschend wenig bekannt. Es ist auch nicht bekannt, ob bereits das Vorhandensein von löslichen Vorstadien dieser zur Aggregation neigenden Protein, die Signaltransduktion von Zellen beeinflusst.
In dieser Studie wurden Amyloidaggregate des auf dem Huntingtin-Protein basierenden Konstrukts HttExon1Q74 und seine noch löslichen Formen verwendet, um deren Wirkung auf die Internalisierung und Rezeptoraktivierung von G-Protein-gekoppelten Rezeptoren (GPCRs) zu analysieren. GPCR bilden die größte Proteinfamilie von Oberflächenrezeptoren in Säugerzellen und spielen eine entscheidende Rolle in der zellulären Signaltransduktion. Es konnte gezeigt werden, dass aggregiertes HttExon1Q74, aber nicht seine noch lösliche Form, die ligandeninduzierte Clathrin-vermittelte Endozytose (CME) verschiedener GPCRs hemmt. Höchstwahrscheinlich beruht dieser inhibitorische Effekt auf einer Sequestrierung des HSC70-Chaperons zu den HttExon1Q74-Aggregaten. In früheren Studien konnte bereits gezeigt werden, dass HSC70 die für CME notwendig ist. Unter Verwendung des VasopressinV1a-Rezeptors (V1aR) und des Corticotropin-Releasing-Faktor-Rezeptors 1 (CRF1R) als Modellproteine, konnte in dieser Arbeit ferner gezeigt werden, dass das Vorhandensein von HttExon1Q74-Aggregaten und die Hemmung der ligandeninduzierten CME zu einer Akkumulation desensibilisierter Rezeptoren in der Plasmamembran führt. Dies stört wiederum die Gq-vermittelte Ca2+-Signalisierung und die Gs-vermittelte cAMP-Signalisierung des V1aR bzw. des CRF1R. Im Gegensatz zu HttExon1Q74-Amyloidaggregaten hemmten lösliches HttExon1Q74 sowie amorphe Proteinaggregate die GPCR-Internalisierung und –Signalisierung nicht. Dies zeigt, dass Amyloidaggregate zelluläre Signaltransduktionsmechanismen spezifisch beeinträchtigen können.
Darüber hinaus konnten vorläufige Experimente zeigen, dass HttExon1Q74-Aggregate eine Erhöhung der Membranexpression des Serotonintranporters SERT verursachen, eines Membranproteins das strukturell und funktionell nicht mit GPCR verwandt ist. Da SERT das wichtigste pharmakologische Zielmolekül bei der Behandlung von depressiven Syndromen ist, könnten diese Daten dazu beitragen, besser zu verstehen, warum Depressionen in sehr frühen Stadien von neurodegenerativen Erkrankungen gehäuft auftreten.
KW  - GPCR
KW  - neurodegenerative
KW  - disease
KW  - protein trafficking
KW  - cell signaling
KW  - Huntington
KW  - GPCR
KW  - Huntington
KW  - Zellsignalisierung
KW  - neurodegenerative Erkrankung
KW  - Proteinhandel
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-506659
ER  - 
TY  - GEN
A1  - Otto, Nils
A1  - Marelja, Zvonimir
A1  - Schoofs, Andreas
A1  - Kranenburg, Holger
A1  - Bittern, Jonas
A1  - Yildirim, Kerem
A1  - Berh, Dimitri
A1  - Bethke, Maria
A1  - Thomas, Silke
A1  - Rode, Sandra
A1  - Risse, Benjamin
A1  - Jiang, Xiaoyi
A1  - Pankratz, Michael
A1  - Leimkühler, Silke
A1  - Klämbt, Christian
T1  - The sulfite oxidase Shopper controls neuronal activity by regulating glutamate homeostasis in Drosophila ensheathing glia
T2  - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe
N2  - Specialized glial subtypes provide support to developing and functioning neural networks. Astrocytes modulate information processing by neurotransmitter recycling and release of neuromodulatory substances, whereas ensheathing glial cells have not been associated with neuromodulatory functions yet. To decipher a possible role of ensheathing glia in neuronal information processing, we screened for glial genes required in the Drosophila central nervous system for normal locomotor behavior. Shopper encodes a mitochondrial sulfite oxidase that is specifically required in ensheathing glia to regulate head bending and peristalsis. shopper mutants show elevated sulfite levels affecting the glutamate homeostasis which then act on neuronal network function. Interestingly, human patients lacking the Shopper homolog SUOX develop neurological symptoms, including seizures. Given an enhanced expression of SUOX by oligodendrocytes, our findings might indicate that in both invertebrates and vertebrates more than one glial cell type may be involved in modulating neuronal activity.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 975 
KW  - molybdenum cofactor deficiency
KW  - blood-brain-barrier
KW  - larval locomotion
KW  - energy-metabolism
KW  - cerebral-cortex
KW  - astrocytes
KW  - behavior
KW  - cells
KW  - transmission
KW  - disease
KW  - Diseases of the nervous system
KW  - Glial biology
KW  - Glial development
KW  - Neurotransmitters
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-426205
SN  - 1866-8372
IS  - 975
ER  - 
TY  - GEN
A1  - Chaykovska, Lyubov
A1  - Heunisch, Fabian
A1  - von Einem, Gina
A1  - Alter, Markus L.
A1  - Hocher, Carl-Friedrich
A1  - Tsuprykov, Oleg
A1  - Dschietzig, Thomas
A1  - Kretschmer, Axel
A1  - Hocher, Berthold
T1  - Urinary vitamin D binding protein and KIM-1 are potent new biomarkers of major adverse renal events in patients undergoing coronary angiography
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Background

Vitamin-D-binding protein (VDBP) is a low molecular weight protein that is filtered through the glomerulus as a 25-(OH) vitamin D 3/VDBP complex. In the normal kidney VDBP is reabsorbed and catabolized by proximal tubule epithelial cells reducing the urinary excretion to trace amounts. Acute tubular injury is expected to result in urinary VDBP loss. The purpose of our study was to explore the potential role of urinary VDBP as a biomarker of an acute renal damage.

Method

We included 314 patients with diabetes mellitus or mild renal impairment undergoing coronary angiography and collected blood and urine before and 24 hours after the CM application. Patients were followed for 90 days for the composite endpoint major adverse renal events (MARE: need for dialysis, doubling of serum creatinine after 90 days, unplanned emergency rehospitalization or death).

Results

Increased urine VDBP concentration 24 hours after contrast media exposure was predictive for dialysis need (no dialysis: 113.06 +/- 299.61ng/ml, n = 303; need for dialysis: 613.07 +/- 700.45 ng/ml, n = 11, Mean +/- SD, p < 0.001), death (no death during follow-up: 121.41 +/- 324.45 ng/ml, n = 306; death during follow-up: 522.01 +/- 521.86 ng/ml, n = 8; Mean +/- SD, p < 0.003) and MARE (no MARE: 112.08 +/- 302.00ng/ml, n = 298; MARE: 506.16 +/- 624.61 ng/ml, n = 16, Mean +/- SD, p < 0.001) during the follow-up of 90 days after contrast media exposure. Correction of urine VDBP concentrations for creatinine excretion confirmed its predictive value and was consistent with increased levels of urinary Kidney Injury Molecule1 (KIM-1) and baseline plasma creatinine in patients with above mentioned complications. The impact of urinary VDBP and KIM-1 on MARE was independent of known CIN risk factors such as anemia, preexisting renal failure, preexisting heart failure, and diabetes.

Conclusions

Urinary VDBP is a promising novel biomarker of major contrast induced nephropathy-associated events 90 days after contrast media exposure.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 558 
KW  - acute kidney injury
KW  - cardiac surgery
KW  - molecule-1 KIM-1
KW  - early diagnosis
KW  - failure
KW  - intervention
KW  - disease
KW  - NGAL
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-411928
SN  - 1866-8372
IS  - 558
ER  - 
TY  - JOUR
A1  - Henkel, Janin
A1  - Coleman Mac Gregor of Inneregny, Charles Dominic
A1  - Schraplau, Anne
A1  - Jöhrens, Korinna
A1  - Weiss, Thomas Siegfried
A1  - Jonas, Wenke
A1  - Schürmann, Annette
A1  - Püschel, Gerhard Paul
T1  - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model
JF  - Scientific Reports
N2  - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.
KW  - suppress VLDL secretion
KW  - mice lacking
KW  - nonalcoholic steatohepatthis
KW  - insulin-resistance
KW  - rat hepatocytes
KW  - kupffer cells
KW  - E-2
KW  - disease
KW  - expression
KW  - accumulation
Y1  - 2018
U6  - https://doi.org/10.1038/s41598-018-34633-y
SN  - 2045-2322
IS  - 8
SP  - 1
EP  - 11
PB  - Nature Research
CY  - London
ER  - 
TY  - GEN
A1  - Henkel, Janin
A1  - Coleman Mac Gregor of Inneregny, Charles Dominic
A1  - Schraplau, Anne
A1  - Jöhrens, Korinna
A1  - Weiss, Thomas Siegfried
A1  - Jonas, Wenke
A1  - Schürmann, Annette
A1  - Püschel, Gerhard Paul
T1  - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 483 
KW  - suppress VLDL secretion
KW  - mice lacking
KW  - nonalcoholic steatohepatthis
KW  - insulin-resistance
KW  - rat hepatocytes
KW  - kupffer cells
KW  - E-2
KW  - disease
KW  - expression
KW  - accumulation
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-420879
SN  - 1866-8372
IS  - 483
ER  - 
TY  - GEN
A1  - Henze, Andrea
A1  - Homann, Thomas
A1  - Rohn, Isabelle
A1  - Aschner, Michael A.
A1  - Link, Christopher D.
A1  - Kleuser, Burkhard
A1  - Schweigert, Florian J.
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin
N2  - The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 312 
KW  - binding
KW  - c. elegans
KW  - cells
KW  - disease
KW  - force-field
KW  - life-span
KW  - menadione
KW  - n-acetyl-cysteine
KW  - protein
KW  - s-glutathionylation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-103674
ER  - 
TY  - JOUR
A1  - Henze, Andrea
A1  - Homann, Thomas
A1  - Rohn, Isabelle
A1  - Aschner, Michael A.
A1  - Link, Christopher D.
A1  - Kleuser, Burkhard
A1  - Schweigert, Florian J.
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin
JF  - Scientific reports
N2  - The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
KW  - n-acetyl-cysteine
KW  - s-glutathionylation
KW  - force-field
KW  - c. elegans
KW  - life-span
KW  - protein
KW  - cells
KW  - menadione
KW  - disease
KW  - binding
Y1  - 2016
U6  - https://doi.org/10.1038/srep37346
SN  - 2045-2322
VL  - 6
PB  - Nature Publishing Group
CY  - London
ER  -