Dataset Information

PTMs of Endogenous Tau in Wildtype and hAPP Transgenic Mice

ABSTRACT: Please Note, if a password is required, please try "a", the generic password for Massive. These data are in support of the manuscript: Post-translational Modifications of Endogenous Tau in Wildtype and Human Amyloid Precursor Protein Transgenic Mice Meaghan Morris*a,b, Giselle M. Knudsen*c, Sumihiro Maedaa,d, Jonathan C. Trinidadc, Alexandra Ianoviciuc, Alma L. Burlingamec, Lennart Muckea,d aGladstone Institute of Neurological Disease, San Francisco, California 94158, USA bBiochemistry, Cellular and Molecular Biology Graduate Program, Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA cMass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA dDepartment of Neurology, University of California, San Francisco, California 94158, USA *These authors contributed equally to this work

INSTRUMENT(S): LTQ Orbitrap, LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Lennart Mucke

PROVIDER: MSV000078796 | MassIVE | Wed Jul 30 12:54:00 BST 2014

REPOSITORIES: MassIVE

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Publications

Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice.

Morris Meaghan M Knudsen Giselle M GM Maeda Sumihiro S Trinidad Jonathan C JC Ioanoviciu Alexandra A Burlingame Alma L AL Mucke Lennart L

Nature neuroscience 20150720 8

The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Reducing tau levels ameliorates AD-related synaptic, network, and behavioral abnormalities in transgenic mice expressing human amyloid precursor protein (hAPP). We used mass spectrometry to characterize the post-translational modification of endogenous tau isolated from wild-type and hAPP mice. We identified seven types of tau modifications at 63 sites ...[more]

PMID: 26192747

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Project description:Mathematical modeling of mutant transferrin-CRM107 molecular conjugates for cancer therapy. Yoon DJ1, Chen KY1, Lopes AM1, Pan AA1, Shiloach J2, Mason AB3, Kamei DT4. Author information 1 Department of Bioengineering, University of California, Los Angeles, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA 90095, USA. 2 Biotechnology Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA. 3 Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA. 4 Department of Bioengineering, University of California, Los Angeles, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA 90095, USA. Electronic address: kamei@seas.ucla.edu. Abstract The transferrin (Tf) trafficking pathway is a promising mechanism for use in targeted cancer therapy due to the overexpression of transferrin receptors (TfRs) on cancerous cells. We have previously developed a mathematical model of the Tf/TfR trafficking pathway to improve the efficiency of Tf as a drug carrier. By using diphtheria toxin (DT) as a model toxin, we found that mutating the Tf protein to change its iron release rate improves cellular association and efficacy of the drug. Though this is an improvement upon using wild-type Tf as the targeting ligand, conjugated toxins like DT are unfortunately still highly cytotoxic at off-target sites. In this work, we address this hurdle in cancer research by developing a mathematical model to predict the efficacy and selectivity of Tf conjugates that use an alternative toxin. For this purpose, we have chosen to study a mutant of DT, cross-reacting material 107 (CRM107). First, we developed a mathematical model of the Tf-DT trafficking pathway by extending our Tf/TfR model to include intracellular trafficking via DT and DT receptors. Using this mathematical model, we subsequently investigated the efficacy of several conjugates in cancer cells: DT and CRM107 conjugated to wild-type Tf, as well as to our engineered mutant Tf proteins (K206E/R632A Tf and K206E/R534A Tf). We also investigated the selectivity of mutant Tf-CRM107 against non-neoplastic cells. Through the use of our mathematical model, we predicted that (i) mutant Tf-CRM107 exhibits a greater cytotoxicity than wild-type Tf-CRM107 against cancerous cells, (ii) this improvement was more drastic with CRM107 conjugates than with DT conjugates, and (iii) mutant Tf-CRM107 conjugates were selective against non-neoplastic cells. These predictions were validated with in vitro cytotoxicity experiments, demonstrating that mutant Tf-CRM107 conjugates is indeed a more suitable therapeutic agent. Validation from in vitro experiments also confirmed that such whole-cell kinetic models can be useful in cancer therapeutic design. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dataset Information

PTMs of Endogenous Tau in Wildtype and hAPP Transgenic Mice

Publications

Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice.

Similar Datasets

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