The Experts below are selected from a list of 59367 Experts worldwide ranked by ideXlab platform
Christopher D Link - One of the best experts on this subject based on the ideXlab platform.
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suppression of in vivo β amyloid peptide toxicity by overexpression of the hsp 16 2 small Chaperone Protein
Journal of Biological Chemistry, 2008Co-Authors: Virginia Fonte, Randal D Kipp, John Yerg, David Merin, Margaret Forrestal, Eileen Wagner, Christine M Roberts, Christopher D LinkAbstract:Abstract Expression of the human β-amyloid peptide (Aβ) in a transgenic Caenorhabditis elegans Alzheimer disease model leads to the induction of HSP-16 Proteins, a family of small heat shock-inducible Proteins homologous to vertebrate αB crystallin. These Proteins also co-localize and co-immunoprecipitate with Aβ in this model (Fonte, V., Kapulkin, V., Taft, A., Fluet, A., Friedman, D., and Link, C. D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 9439–9444). To investigate the molecular basis and biological function of this interaction between HSP-16 and Aβ, we generated transgenic C. elegans animals with high level, constitutive expression of HSP-16.2. We find that constitutive expression of wild type, but not mutant, HSP-16.2 partially suppresses Aβ toxicity. Wild type Aβ-(1–42), but not Aβ single chain dimer, was observed to become sequestered in HSP-16.2-containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and Aβ in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but it did not reduce the overall accumulation of Aβ peptide or alter the pattern of the predominant oligomeric species. Studies with recombinant HSP-16.2 demonstrated that HSP-16.2 can bind directly to Aβ in vitro, with a preferential affinity for oligomeric Aβ species. This interaction between Aβ and HSP-16.2 also influences the formation of Aβ oligomers in in vitro assays. These studies are consistent with a model in which small Chaperone Proteins reduce Aβ toxicity by interacting directly with the Aβ peptide and altering its oligomerization pathways, thereby reducing the formation of a minor toxic species.
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suppression of in vivo β amyloid peptide toxicity by overexpression of the hsp 16 2 small Chaperone Protein
Journal of Biological Chemistry, 2008Co-Authors: Virginia Fonte, Randal D Kipp, John Yerg, David Merin, Margaret Forrestal, Eileen Wagner, Christine M Roberts, Christopher D LinkAbstract:Expression of the human beta-amyloid peptide (Abeta) in a transgenic Caenorhabditis elegans Alzheimer disease model leads to the induction of HSP-16 Proteins, a family of small heat shock-inducible Proteins homologous to vertebrate alphaB crystallin. These Proteins also co-localize and co-immunoprecipitate with Abeta in this model (Fonte, V., Kapulkin, V., Taft, A., Fluet, A., Friedman, D., and Link, C. D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 9439-9444). To investigate the molecular basis and biological function of this interaction between HSP-16 and Abeta, we generated transgenic C. elegans animals with high level, constitutive expression of HSP-16.2. We find that constitutive expression of wild type, but not mutant, HSP-16.2 partially suppresses Abeta toxicity. Wild type Abeta-(1-42), but not Abeta single chain dimer, was observed to become sequestered in HSP-16.2-containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and Abeta in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but it did not reduce the overall accumulation of Abeta peptide or alter the pattern of the predominant oligomeric species. Studies with recombinant HSP-16.2 demonstrated that HSP-16.2 can bind directly to Abeta in vitro, with a preferential affinity for oligomeric Abeta species. This interaction between Abeta and HSP-16.2 also influences the formation of Abeta oligomers in in vitro assays. These studies are consistent with a model in which small Chaperone Proteins reduce Abeta toxicity by interacting directly with the Abeta peptide and altering its oligomerization pathways, thereby reducing the formation of a minor toxic species.
Malcolm K Horne - One of the best experts on this subject based on the ideXlab platform.
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endoplasmic reticulum stress and induction of the unfolded Protein response in human sporadic amyotrophic lateral sclerosis
Neurobiology of Disease, 2008Co-Authors: Julie D Atkin, Manual A Farg, Adam K Walker, Catriona Mclean, Doris Tomas, Malcolm K HorneAbstract:The unfolded Protein response (UPR) is induced at symptom onset and disease end stage in rodent models of familial amyotrophic lateral sclerosis (ALS) that express superoxide dismutase (SOD1) mutations. However, ninety percent of human ALS is sporadic and mutations in SOD1 account for only 2% of total ALS. Here we show that a full UPR, including induction of stress sensor kinases, Chaperones and apoptotic mediators, is also present in spinal cords of human patients with sporadic disease. Furthermore, the UPR Chaperone Protein disulphide isomerase (PDI) was present in CSF and was aggregated and widely distributed throughout the motor neurons of these patients. We also show up-regulation of UPR prior to the onset of symptoms in SOD1 rodents, implying an active role in disease. This study offers new insights into pathogenesis, placing ER stress onto a generic pathophysiology for ALS.
Brent R Stockwell - One of the best experts on this subject based on the ideXlab platform.
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inhibitors of Protein disulfide isomerase suppress apoptosis induced by misfolded Proteins
Nature Chemical Biology, 2010Co-Authors: Benjamin G Hoffstrom, Anna Kaplan, Reka Letso, Ralf S Schmid, Gregory J Turmel, Brent R Stockwell, Donald C LoAbstract:Expression of a Huntington's-disease variant of huntingtin Protein causes accumulation of the Chaperone Protein disulfide isomerase. This Protein is the target of compounds obtained from screening for those that can alleviate cell death promoted by the mutant huntingtin, and represents a new connection between Protein misfolding and cell death.
Marcel Deckert - One of the best experts on this subject based on the ideXlab platform.
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the Chaperone Protein 14 3 3 interacts with 3bp2 sh3bp2 and regulates its adapter function
Journal of Biological Chemistry, 2003Co-Authors: Isabelle Foucault, Yun-cai Liu, Alain Bernard, Marcel DeckertAbstract:Abstract Lymphocyte stimulation by immunoreceptors is achieved through the activation of multiple signaling pathways leading to cytokine gene transcription. Adapter Proteins are critical signaling components that can integrate multiple pathways by allowing the assembly of multimolecular signaling complexes. We previously showed that the cytoplasmic adapter 3BP2 (also known as SH3BP2) promotes NFAT/AP-1 transcriptional activities in T cells through the activation of Ras- and calcineurin-dependent pathways. However, the molecular mechanisms by which 3BP2/SH3BP2 regulates cell signaling and activation remain poorly documented. In this study, using a combination of yeast two-hybrid analysis and biochemical approaches, we present evidence for a physical interaction between 3BP2 and the Chaperone Protein 14-3-3. This interaction was direct and constitutively detected in yeast and in mammalian cells. Phorbol ester, pervanadate, and forskolin/isobutylmethylxanthine stimulations enhanced this interaction, as well as co-expression of constitutive active mutants of serine/threonine kinases, including Protein kinase C. We found that dephosphorylation of 3BP2 by alkaline phosphatase disrupted its interaction with 14-3-3 and that 3BP2 was a substrate of purified Protein kinase C in vitro, suggesting that the phosphorylation of 3BP2 by upstream kinases was required for 14-3-3 binding. Using deletion mutants of 3BP2, two 14-3-3 binding domains were mapped to two proline-rich (residues 201–240 and 270–310) domains of 3BP2. These domains were shown to contain two 14-3-3 consensus binding motifs. We identified residues Ser225 and Ser277 of 3BP2 as being essential for interaction with 14-3-3 family Proteins, optimal 3BP2 serine phosphorylation, and then for 3BP2-dependent function. Indeed, a 3BP2 mutant Protein incapable of binding 14-3-3 showed increased capacity to stimulate NFAT transcriptional activities, suggesting that 14-3-3 binding to 3BP2 negatively regulates 3BP2 adapter function in lymphocytes.
Virginia Fonte - One of the best experts on this subject based on the ideXlab platform.
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suppression of in vivo β amyloid peptide toxicity by overexpression of the hsp 16 2 small Chaperone Protein
Journal of Biological Chemistry, 2008Co-Authors: Virginia Fonte, Randal D Kipp, John Yerg, David Merin, Margaret Forrestal, Eileen Wagner, Christine M Roberts, Christopher D LinkAbstract:Abstract Expression of the human β-amyloid peptide (Aβ) in a transgenic Caenorhabditis elegans Alzheimer disease model leads to the induction of HSP-16 Proteins, a family of small heat shock-inducible Proteins homologous to vertebrate αB crystallin. These Proteins also co-localize and co-immunoprecipitate with Aβ in this model (Fonte, V., Kapulkin, V., Taft, A., Fluet, A., Friedman, D., and Link, C. D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 9439–9444). To investigate the molecular basis and biological function of this interaction between HSP-16 and Aβ, we generated transgenic C. elegans animals with high level, constitutive expression of HSP-16.2. We find that constitutive expression of wild type, but not mutant, HSP-16.2 partially suppresses Aβ toxicity. Wild type Aβ-(1–42), but not Aβ single chain dimer, was observed to become sequestered in HSP-16.2-containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and Aβ in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but it did not reduce the overall accumulation of Aβ peptide or alter the pattern of the predominant oligomeric species. Studies with recombinant HSP-16.2 demonstrated that HSP-16.2 can bind directly to Aβ in vitro, with a preferential affinity for oligomeric Aβ species. This interaction between Aβ and HSP-16.2 also influences the formation of Aβ oligomers in in vitro assays. These studies are consistent with a model in which small Chaperone Proteins reduce Aβ toxicity by interacting directly with the Aβ peptide and altering its oligomerization pathways, thereby reducing the formation of a minor toxic species.
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suppression of in vivo β amyloid peptide toxicity by overexpression of the hsp 16 2 small Chaperone Protein
Journal of Biological Chemistry, 2008Co-Authors: Virginia Fonte, Randal D Kipp, John Yerg, David Merin, Margaret Forrestal, Eileen Wagner, Christine M Roberts, Christopher D LinkAbstract:Expression of the human beta-amyloid peptide (Abeta) in a transgenic Caenorhabditis elegans Alzheimer disease model leads to the induction of HSP-16 Proteins, a family of small heat shock-inducible Proteins homologous to vertebrate alphaB crystallin. These Proteins also co-localize and co-immunoprecipitate with Abeta in this model (Fonte, V., Kapulkin, V., Taft, A., Fluet, A., Friedman, D., and Link, C. D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 9439-9444). To investigate the molecular basis and biological function of this interaction between HSP-16 and Abeta, we generated transgenic C. elegans animals with high level, constitutive expression of HSP-16.2. We find that constitutive expression of wild type, but not mutant, HSP-16.2 partially suppresses Abeta toxicity. Wild type Abeta-(1-42), but not Abeta single chain dimer, was observed to become sequestered in HSP-16.2-containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and Abeta in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but it did not reduce the overall accumulation of Abeta peptide or alter the pattern of the predominant oligomeric species. Studies with recombinant HSP-16.2 demonstrated that HSP-16.2 can bind directly to Abeta in vitro, with a preferential affinity for oligomeric Abeta species. This interaction between Abeta and HSP-16.2 also influences the formation of Abeta oligomers in in vitro assays. These studies are consistent with a model in which small Chaperone Proteins reduce Abeta toxicity by interacting directly with the Abeta peptide and altering its oligomerization pathways, thereby reducing the formation of a minor toxic species.