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Choi, Youngseon,Cho, Yoojin,Kim, Minjung,Grailhe, Regis,Song, Rita American Chemical Society 2012 ANALYTICAL CHEMISTRY - Vol.84 No.20
<P>We have developed a novel fluorogenic nanoprobe prepared from the assembly of CdSe/ZnS quantum dot (QD) and gold (Au) nanoparticles in which QD was conjugated with a specifically designed β-secretase (BACE1) substrate peptide, which was allowed to bind to the Ni-nitrilotriacetate (Ni-NTA) modified Au nanoparticles. This coordination-mediated binding of the QD with Au nanoparticles via Ni-NTA-histidine (His) interaction resulted in highly efficient quenching of QD fluorescence through a distance-dependent fluorescence resonance energy transfer (FRET) phenomenon. The prequenched QD-Au assembly recovered the fluorescence in the presence of the BACE1 enzyme after incubation in vitro. The high quenching efficiency of AuNP and robust QD fluorescence signal recovery upon BACE1 enzymatic digestion enabled us to visualize BACE1 activity in living cells, which further allowed us to generate the half maximal inhibitory concentration (IC<SUB>50</SUB>) values for BACE1 inhibitors in the cell-based assay utilizing a high throughput system (HTS). These results suggest the potential application of QD-AuNP assembly toward the HTS drug screening system as a robust and efficient probe to identify active molecules in BACE1-related diseases such as Alzheimer’s disease.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/ancham/2012/ancham.2012.84.issue-20/ac301574b/production/images/medium/ac-2012-01574b_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ac301574b'>ACS Electronic Supporting Info</A></P>
Glioblastoma-secreted soluble CD44 activates tau pathology in the brain
임성수,김도희,주신영,신슬기,조일주,박성혜,Regis Grailhe,이철주,김윤경 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-
During aggressive tumor growth and migration, glioblastoma cells secrete diverse molecules and adhesion proteins to the extracellular matrix. Yet, the biochemical effects of the glioblastoma secretome in the brain remain largely unknown. Here we show that soluble CD44 secreted from glioblastoma cells induces neuronal degeneration through the activation of tau pathology in the brain. Glioblastoma-xenograft tissues showed a number of degenerating neurons bearing highly phosphorylated tau. Through a series of secretome-analyses, we identified that soluble CD44 was the responsible protein inducing tau phosphorylation and aggregation (EC50 = 19.1 ng/mL). The treatment of sCD44 to primary hippocampal neurons-induced tau hyperphosphorylation, leading to neuronal degeneration. Also, the injection of sCD44 into the brains of tau transgenic mice induced tau hyper-phosphorylation in hippocampal neurons. Altogether, our data suggest a neurodegenerative role of sCD44 in promoting tau pathology and serving as a molecular link between glioblastoma and neurodegeneration.
Kim, Junwon,Park, Hye-Young,Kim, Jaeseung,Ryu, Jiyoung,Kwon, Do Yoon,Grailhe, Regis,Song, Rita Royal Society of Chemistry 2008 Chemical communications Vol.2008 No.16
<P>Ni–nitrilotriacetic acid (NTA) functionalized CdSe/ZnS quantum dots (QDs) were exploited as a site-specific labeling agent of histidine-tagged biomolecules in live cells; the QDs were found to be water-soluble, aggregation free and stable for several months.</P> <P>Graphic Abstract</P><P>Ni–nitrilotriacetic acid (NTA) functionalized quantum dots (QDs) were exploited as a site-specific labeling agent of histidine-tagged proteins in live cells. The Ni–NTA modified QDs were found to be water-soluble, aggregation free and stable for several months. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=b719434j'> </P>
Kim, Jiho,Lee, Joohyun,Kwon, Doyoon,Lee, Honggun,Grailhe, Regis Royal Society of Chemistry 2011 Molecular bioSystems Vol.7 No.11
<P>Fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) are extensively used to analyze protein interactions occurring in living cells. Although these two techniques are broadly applied in cellular biology, comparative analysis of their strengths and limitations is lacking. To this end, we analyzed a small network of proteins involved in the amyloidogenic processing of the Alzheimer β-amyloid precursor using FRET based cytometry, BRET, and fluorescence lifetime imaging microscopy (FLIM). Using all three methods, we were able to detect the interactions of the amyloid precursor protein with APBB1, APBB2, and APP itself. And we found an unreported interacting pair, APP–APH1A. In addition, we show that these four interacting pairs exhibit a strong FRET correlation with the acceptor/donor expression ratios. Overall the FRET based cytometry was the most sensitive and reliable approach to screen for new interacting proteins. Therefore, we applied FRET based cytometry to study competitive binding of two proteins, APBB1 and APBB2, with the same APP target.</P> <P>Graphic Abstract</P><P>Comparative BRET and FRET screening of Alzheimer protein network shows robustness of FRET cytometry and a novel APP–APH1A interacting pair. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c1mb05279a'> </P>
The use of cyan fluorescent protein variants with a distinctive lifetime signature
Kim, Jiho,Kwon, DoYoon,Lee, Joohyun,Pasquier, Hé,lè,ne,Grailhe, Regis Royal Society of Chemistry 2009 Molecular bioSystems Vol.5 No.2
<P>The use of Cyan Fluorescent Proteins, with a distinctive lifetime signature, opens up new alternatives to track and semi-quantify the relative expression of proteins <I>in vivo</I> using a single excitation source and emission channel.</P> <P>Graphic Abstract</P><P>The use of Cyan Fluorescent Proteins, with a distinctive lifetime signature, opens up new alternatives to track and semi-quantify the relative expression of proteins <I>in vivo</I> using a single excitation source and emission channel. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=b815445g'> </P>
Kim, Jiho,Lee, Honggun,Lee, Joo Hyun,Kwon, Do-yoon,Genovesio, Auguste,Fenistein, Denis,Ogier, Arnaud,Brondani, Vincent,Grailhe, Regis American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.21
<P>More than 100 copper/zinc superoxide dismutase 1 (SOD1) genetic mutations have been characterized. These mutations lead to the death of motor neurons in ALS. In its native form, the SOD1 protein is expressed as a homodimer in the cytosol. <I>In vitro</I> studies have shown that SOD1 mutations impair the dimerization kinetics of the protein, and <I>in vivo</I> studies have shown that SOD1 forms aggregates in patients with familial forms of ALS. In this study, we analyzed WT SOD1 and 9 mutant (mt) forms of the protein by non-invasive fluorescence techniques. Using microscopic techniques such as fluorescence resonance energy transfer, fluorescence complementation, image-based quantification, and fluorescence correlation spectroscopy, we studied SOD1 dimerization, oligomerization, and aggregation. Our results indicate that SOD1 mutations lead to an impairment in SOD1 dimerization and, subsequently, affect protein aggregation. We also show that SOD1 WT and mt proteins can dimerize. However, aggregates are predominantly composed of SOD1 mt proteins.</P>