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830 results on '"Willemsen, Rob"'

202. Proteomic Profiling of Exosomes Leads to the Identification of Novel Biomarkers for Prostate Cancer

Author

Duijvesz, Diederick, Burnum-Johnson, KE, Gritsenko, MA, Hoogland, Marije, Berg, Mirella, Willemsen, Rob, Luider, Theo, Pasa-Tolic, L, Jenster, Guido, Duijvesz, Diederick, Burnum-Johnson, KE, Gritsenko, MA, Hoogland, Marije, Berg, Mirella, Willemsen, Rob, Luider, Theo, Pasa-Tolic, L, and Jenster, Guido

Abstract

Background: Current markers for prostate cancer, such as PSA lack specificity. Therefore, novel biomarkers are needed. Unfortunately, the complexity of body fluids often hampers biomarker discovery. An attractive alternative approach is the isolation of small vesicles, i.e. exosomes, similar to 100 nm, which contain proteins that are specific to the tissue from which they are derived and therefore can be considered as treasure chests for disease-specific biomarker discovery. Materials and Methods: Exosomes were isolated from 2 immortalized primary prostate epithelial cells (PNT2C2 and RWPE-1) and 2 PCa cell lines (PC346C and VCaP) by ultracentrifugation. After tryptic digestion, proteomic analyses utilized a nanoLC coupled with an LTQ-Orbitrap operated in tandem MS (MS/MS) mode. Accurate Mass and Time (AMT) tag approach was employed for peptide identification and quantitation. Candidate biomarkers were validated by Western blotting and Immunohistochemistry. Results: Proteomic characterization resulted in the identification of 248, 233, 169, and 216 proteins by at least 2 peptides in exosomes from PNT2C2, RWPE-1, PC346C, and VCaP, respectively. Statistical analyses revealed 52 proteins differently abundant between PCa and control cells, 9 of which were more abundant in PCa. Validation by Western blotting confirmed a higher abundance of FASN, XPO1 and PDCD6IP (ALIX) in PCa exosomes. Conclusions: Identification of exosomal proteins using high performance LC-FTMS resulted in the discovery of PDCD6IP, FASN, XPO1 and ENO1 as new candidate biomarkers for prostate cancer.

Published
2013

208. Dopaminergic Neuronal Loss and Dopamine-Dependent Locomotor Defects in Fbxo7-Deficient Zebrafish

Author

Zhao, Tianna, Zondervan - van der Linde, Herma, Severijnen, Lies-anne, Oostra, Ben, Willemsen, Rob, Bonifati, Vincenzo, Zhao, Tianna, Zondervan - van der Linde, Herma, Severijnen, Lies-anne, Oostra, Ben, Willemsen, Rob, and Bonifati, Vincenzo

Abstract

Recessive mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, a Mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15 remain unknown. No animal models of this disease exist. Here, we report the generation of a vertebrate model of PARK15 in zebrafish. We first show that the zebrafish Fbxo7 homolog protein (zFbxo7) is expressed abundantly in the normal zebrafish brain. Next, we used two zFbxo7-specific morpholinos (targeting protein translation and mRNA splicing, respectively), to knock down the zFbxo7 expression. The injection of either of these zFbxo7-specific morpholinos in the fish embryos induced a marked decrease in the zFbxo7 protein expression, and a range of developmental defects. Furthermore, whole-mount in situ mRNA hybridization showed abnormal patterning and significant decrease in the number of diencephalic tyrosine hydroxylase-expressing neurons, corresponding to the human nigrostriatal or ventral tegmental dopaminergic neurons. Of note, the number of the dopamine transporter-expressing neurons was much more severely depleted, suggesting dopaminergic dysfunctions earlier and larger than those due to neuronal loss. Last, the zFbxo7 morphants displayed severe locomotor disturbances (bradykinesia), which were dramatically improved by the dopaminergic agonist apomorphine. The severity of these morphological and behavioral abnormalities correlated with the severity of zFbxo7 protein deficiency. Moreover, the effects of the co-injection of zFbxo7- and p53-specific morpholinos were similar to those obtained with zFbxo7-specific morpholinos alone, supporting further the contention that the observed phenotypes were specifically due to the knock down of zFbxo7. In conclusion, this novel vertebrate model reproduces pathologic and behavioral hallmarks of human parkinsonism (dopaminergic neuronal loss an

Published
2012

211. Differential usage of transcriptional start sites and polyadenylation sites in FMR1 premutation alleles(dagger)

Author

Tassone, F, De Rubeis, S, Carosi, C, La Fata, G, Serpa, G, Raske, C, Willemsen, Rob, Hagerman, PJ, Bagni, C, Tassone, F, De Rubeis, S, Carosi, C, La Fata, G, Serpa, G, Raske, C, Willemsen, Rob, Hagerman, PJ, and Bagni, C

Abstract

5'- and 3'-untranslated regions (UTRs) are important regulators of gene expression and play key roles in disease progression and susceptibility. The 5'-UTR of the fragile X mental retardation 1 (FMR1) gene contains a CGG repeat element that is expanded (> 200 CGG repeats; full mutation) and methylated in fragile X syndrome (FXS), the most common form of inherited intellectual disability (ID) and known cause of autism. Significant phenotypic involvement has also emerged in some individuals with the premutation (55-200 CGG repeats), including fragile X-associated premature ovarian insufficiency (FXPOI) in females, and the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), in older adult carriers. Here, we show that FMR1 mRNA in human and mouse brain is expressed as a combination of multiple isoforms that use alternative transcriptional start sites and different polyadenylation sites. Furthermore, we have identified a novel human transcription start site used in brain but not in lymphoblastoid cells, and have detected FMR1 isoforms generated through the use of both canonical and non-canonical polyadenylation signals. Importantly, in both human and mouse, a specific regulation of the UTRs is observed in brain of FMR1 premutation alleles, suggesting that the transcript variants may play a role in premutation-related pathologies.

Published
2011

212. Loss of Nuclear Activity of the FBXO7 Protein in Patients with Parkinsonian-Pyramidal Syndrome (PARK15)

Author

Zhao, TN, Graaff, Esther, Breedveld, Guido, Loda, A (Agnese), Severijnen, Lies-anne, Wouters, Cokkie, Verheijen, Frans, Dekker, MCJ (Marieke), Montagna, P, Willemsen, Rob, Oostra, Ben, Bonifati, Vincenzo, Zhao, TN, Graaff, Esther, Breedveld, Guido, Loda, A (Agnese), Severijnen, Lies-anne, Wouters, Cokkie, Verheijen, Frans, Dekker, MCJ (Marieke), Montagna, P, Willemsen, Rob, Oostra, Ben, and Bonifati, Vincenzo

Abstract

Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PAR

Published
2011

215. Generation and Characterization of Fmr1 Knockout Zebrafish

Author

den Broeder, MJ, Zondervan - van der Linde, Herma, Brouwer, JR (Jaap), Oostra, Ben, Willemsen, Rob, Ketting, RF, den Broeder, MJ, Zondervan - van der Linde, Herma, Brouwer, JR (Jaap), Oostra, Ben, Willemsen, Rob, and Ketting, RF

Abstract

Fragile X syndrome (FXS) is one of the most common known causes of inherited mental retardation. The gene mutated in FXS is named FMR1, and is well conserved from human to Drosophila. In order to generate a genetic tool to study FMR1 function during vertebrate development, we generated two mutant alleles of the fmr1 gene in zebrafish. Both alleles produce no detectable Fmr protein, and produce viable and fertile progeny with lack of obvious phenotypic features. This is in sharp contrast to published results based on morpholino mediated knock-down of fmr1, reporting defects in craniofacial development and neuronal branching in embryos. These phenotypes we specifically addressed in our knock-out animals, revealing no significant deviations from wild-type animals, suggesting that the published morpholino based fmr1 phenotypes are potential experimental artifacts. Therefore, their relation to fmr1 biology is questionable and morpholino induced fmr1 phenotypes should be avoided in screens for potential drugs suitable for the treatment of FXS. Importantly, a true genetic zebrafish model is now available which can be used to study FXS and to derive potential drugs for FXS treatment.

Published
2009

216. Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferation–differentiation balance early in life and optic nerve degeneration at old age

Author

Iglesias, Adriana I., primary, Springelkamp, Henriët, additional, van der Linde, Herma, additional, Severijnen, Lies-Anne, additional, Amin, Najaf, additional, Oostra, Ben, additional, Kockx, Christel E. M., additional, van den Hout, Mirjam C. G. N., additional, van IJcken, Wilfred F. J., additional, Hofman, Albert, additional, Uitterlinden, André G., additional, Verdijk, Rob M., additional, Klaver, Caroline C. W., additional, Willemsen, Rob, additional, and van Duijn, Cornelia M., additional

Published
2013
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217. Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome

Author

Sellier, Chantal, primary, Freyermuth, Fernande, additional, Tabet, Ricardos, additional, Tran, Tuan, additional, He, Fang, additional, Ruffenach, Frank, additional, Alunni, Violaine, additional, Moine, Herve, additional, Thibault, Christelle, additional, Page, Adeline, additional, Tassone, Flora, additional, Willemsen, Rob, additional, Disney, Matthew D., additional, Hagerman, Paul J., additional, Todd, Peter K., additional, and Charlet-Berguerand, Nicolas, additional

Published
2013
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228. NPHP4 Variants Are Associated With Pleiotropic Heart Malformations

Author

French, Vanessa M., primary, van de Laar, Ingrid M.B.H., additional, Wessels, Marja W., additional, Rohe, Christan, additional, Roos-Hesselink, Jolien W., additional, Wang, Guangliang, additional, Frohn-Mulder, Ingrid M.E., additional, Severijnen, Lies-Anne, additional, de Graaf, Bianca M., additional, Schot, Rachel, additional, Breedveld, Guido, additional, Mientjes, Edwin, additional, van Tienhoven, Marianne, additional, Jadot, Elodie, additional, Jiang, Zhengxin, additional, Verkerk, Annemieke, additional, Swagemakers, Sigrid, additional, Venselaar, Hanka, additional, Rahimi, Zohreh, additional, Najmabadi, Hossein, additional, Meijers-Heijboer, Hanne, additional, de Graaff, Esther, additional, Helbing, Wim A., additional, Willemsen, Rob, additional, Devriendt, Koen, additional, Belmont, John W., additional, Oostra, Ben A., additional, Amack, Jeffrey D., additional, and Bertoli-Avella, Aida M., additional

Published
2012
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229. Species-Dependent Posttranscriptional Regulation of NOS1 by FMRP in the Developing Cerebral Cortex

Author

Kwan, Kenneth Y., primary, Lam, Mandy M.S., additional, Johnson, Matthew B., additional, Dube, Umber, additional, Shim, Sungbo, additional, Rašin, Mladen-Roko, additional, Sousa, André M.M., additional, Fertuzinhos, Sofia, additional, Chen, Jie-Guang, additional, Arellano, Jon I., additional, Chan, Daniel W., additional, Pletikos, Mihovil, additional, Vasung, Lana, additional, Rowitch, David H., additional, Huang, Eric J., additional, Schwartz, Michael L., additional, Willemsen, Rob, additional, Oostra, Ben A., additional, Rakic, Pasko, additional, Heffer, Marija, additional, Kostović, Ivica, additional, Judaš, Milos, additional, and Šestan, Nenad, additional

Published
2012
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230. Mutations in SLC30A10 Cause Parkinsonism and Dystonia with Hypermanganesemia, Polycythemia, and Chronic Liver Disease

Author

Quadri, Marialuisa, primary, Federico, Antonio, additional, Zhao, Tianna, additional, Breedveld, Guido J., additional, Battisti, Carla, additional, Delnooz, Cathérine, additional, Severijnen, Lies-Anne, additional, Di Toro Mammarella, Lara, additional, Mignarri, Andrea, additional, Monti, Lucia, additional, Sanna, Antioco, additional, Lu, Peng, additional, Punzo, Francesca, additional, Cossu, Giovanni, additional, Willemsen, Rob, additional, Rasi, Fabrizio, additional, Oostra, Ben A., additional, van de Warrenburg, Bart P., additional, and Bonifati, Vincenzo, additional

Published
2012
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233. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions

Author

Simón-Sánchez, Javier, primary, Dopper, Elise G. P., additional, Cohn-Hokke, Petra E., additional, Hukema, Renate K., additional, Nicolaou, Nayia, additional, Seelaar, Harro, additional, de Graaf, J. Roos A., additional, de Koning, Inge, additional, van Schoor, Natasja M., additional, Deeg, Dorly J. H., additional, Smits, Marion, additional, Raaphorst, Joost, additional, van den Berg, Leonard H., additional, Schelhaas, Helenius J., additional, De Die-Smulders, Christine E. M., additional, Majoor-Krakauer, Danielle, additional, Rozemuller, Annemieke J. M., additional, Willemsen, Rob, additional, Pijnenburg, Yolande A. L., additional, Heutink, Peter, additional, and van Swieten, John C., additional

Published
2012
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234. Mouse models of fragile X-related disorders

Author

Willemsen, Rob and Kooy, R. Frank

Abstract

The fragile X-related disorders are an important group of hereditary disorders that are caused by expanded CGG repeats in the 5′ untranslated region of the FMR1 gene or by mutations in the coding sequence of this gene. Two categories of pathological CGG repeats are associated with these disorders, full mutation alleles and shorter premutation alleles. Individuals with full mutation alleles develop fragile X syndrome, which causes autism and intellectual disability, whereas those with premutation alleles, which have shorter CGG expansions, can develop fragile X-associated tremor/ataxia syndrome, a progressive neurodegenerative disease. Thus, fragile X-related disorders can manifest as neurodegenerative or neurodevelopmental disorders, depending on the size of the repeat expansion. Here, we review mouse models of fragile X-related disorders and discuss how they have informed our understanding of neurodegenerative and neurodevelopmental disorders. We also assess the translational value of these models for developing rational targeted therapies for intellectual disability and autism disorders.

Published
2023
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236. Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice

Author

Hunsaker, Michael R., primary, Greco, Claudia M., additional, Spath, Marian A., additional, Smits, Arie P. T., additional, Navarro, Celestine S., additional, Tassone, Flora, additional, Kros, Johan M., additional, Severijnen, Lies-Anne, additional, Berry-Kravis, Elizabeth M., additional, Berman, Robert F., additional, Hagerman, Paul J., additional, Willemsen, Rob, additional, Hagerman, Randi J., additional, and Hukema, Renate K., additional

Published
2011
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238. AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome

Author

Levenga, Josien, primary, Hayashi, Shigemi, additional, de Vrij, Femke M.S., additional, Koekkoek, Sebastiaan K., additional, van der Linde, Herma C., additional, Nieuwenhuizen, Ingeborg, additional, Song, Cheng, additional, Buijsen, Ronald A.M., additional, Pop, Andreea S., additional, GomezMancilla, Baltazar, additional, Nelson, David L., additional, Willemsen, Rob, additional, Gasparini, Fabrizio, additional, and Oostra, Ben A., additional

Published
2011
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242. Loss of Nuclear Activity of the FBXO7 Protein in Patients with Parkinsonian-Pyramidal Syndrome (PARK15)

Author

Zhao, Tianna, primary, De Graaff, Esther, additional, Breedveld, Guido J., additional, Loda, Agnese, additional, Severijnen, Lies-Anne, additional, Wouters, Cokkie H., additional, Verheijen, Frans W., additional, Dekker, Marieke C. J., additional, Montagna, Pasquale, additional, Willemsen, Rob, additional, Oostra, Ben A., additional, and Bonifati, Vincenzo, additional

Published
2011
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243. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Author

van de Laar, Ingrid M B H, primary, Oldenburg, Rogier A, additional, Pals, Gerard, additional, Roos-Hesselink, Jolien W, additional, de Graaf, Bianca M, additional, Verhagen, Judith M A, additional, Hoedemaekers, Yvonne M, additional, Willemsen, Rob, additional, Severijnen, Lies-Anne, additional, Venselaar, Hanka, additional, Vriend, Gert, additional, Pattynama, Peter M, additional, Collée, Margriet, additional, Majoor-Krakauer, Danielle, additional, Poldermans, Don, additional, Frohn-Mulder, Ingrid M E, additional, Micha, Dimitra, additional, Timmermans, Janneke, additional, Hilhorst-Hofstee, Yvonne, additional, Bierma-Zeinstra, Sita M, additional, Willems, Patrick J, additional, Kros, Johan M, additional, Oei, Edwin H G, additional, Oostra, Ben A, additional, Wessels, Marja W, additional, and Bertoli-Avella, Aida M, additional

Published
2011
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