Search Results to David A. Harris, MD, PhD

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Research Expertise & Professional Interests Expertise in prion diseases and Alzheimer’s disease. My laboratory investigates the molecular and cellular mechanisms underlying two classes of human neurodegenerative disorders: prion diseases and Alzheimer’s disease. Alzheimer’s disease afflicts 5 million people in the U.S., a number that will increase dramatically as the population ages. Prion diseases are much rarer, but are of great public health concern because of the global emergence of bovine spongiform encephalopathy (“mad cow disease”), and its likely transmission to human beings. Moreover, prions exemplify a novel mechanism of biological information transfer based on self-propagating changes in protein conformation, rather than on inheritance of nucleic acid sequence. Prion and Alzheimer’s diseases are part of a larger group of neurodegenerative disorders, including Parkinson’s, Huntington’s and several other diseases, which are due to protein misfolding and aggregation. A prion-like process may be responsible for the spread of brain pathology in several of these disorders, and there is evidence that the prion protein itself may serve as a cell-surface receptor mediating the neurotoxic effects of multiple kinds of misfolded protein. Thus, our work on prion and Alzheimer’s diseases will likely provide important insights into a number of other chronic, neurodegenerative disorders. Our work has several broad objectives. First, we wish to understand how the cellular form of the prion protein (PrPC) is converted into the infectious form (PrPSc). To address this question, we have investigated the cellular localization and trafficking of both PrPC and PrPSc, the nature of their association with cell membranes, as well as the molecular features of the conversion process itself. Second, we want to understand how prions and other misfolded protein aggregates cause neurodegeneration, neuronal death and synaptic dysfunction. In this regard, we seek to identify what molecular forms of PrP and the Alzheimer’s Aß peptide represent the proximate neurotoxic species, and what receptors and cellular pathways they activate that lead to pathology. Third, we aim to use our knowledge of the cell biology of prion and Alzheimer’s diseases to develop drug molecules for treatment of these disorders. We utilize a range of experimental systems and models, including transgenic mice, cultured mammalian cells, yeast (S. cerevisiae), and in vitro systems. We employ a wide variety of techniques, including protein chemistry, light and electron microscopy, mouse transgenetics, high-throughput screening, neuropathological analysis, biophysical techniques (surface plasmon resonance, NMR, X-ray crystallography), electrophysiology (patch-clamping), medicinal chemistry, and drug discovery approaches.

One or more keywords matched the following items that are connected to Harris, David

Item TypeName
Concept Carrier Proteins
Concept Glial Fibrillary Acidic Protein
Concept Heat-Shock Proteins
Concept Luminescent Proteins
Concept Membrane Proteins
Concept Microfilament Proteins
Concept Models, Structural
Concept Nerve Tissue Proteins
Concept Protein Binding
Concept Protein Conformation
Concept Protein Denaturation
Concept Protein Processing, Post-Translational
Concept Protein-Tyrosine Kinases
Concept Proteins
Concept Recombinant Fusion Proteins
Concept Recombinant Proteins
Concept Structure-Activity Relationship
Concept Protein Biosynthesis
Concept Viral Proteins
Concept Cysteine Proteinase Inhibitors
Concept Protein Structure, Secondary
Concept Protein Structure, Tertiary
Concept Protein Folding
Concept PrPSc Proteins
Concept PrPC Proteins
Concept GTP-Binding Proteins
Concept Proto-Oncogene Proteins c-bcl-2
Concept Protein Isoforms
Concept Sequence Analysis, Protein
Concept rab GTP-Binding Proteins
Concept Protein Structure, Quaternary
Concept Protein Transport
Concept Protein Sorting Signals
Concept Cation Transport Proteins
Concept Saccharomyces cerevisiae Proteins
Concept Xenopus Proteins
Concept Zebrafish Proteins
Concept Avian Proteins
Concept p38 Mitogen-Activated Protein Kinases
Concept Green Fluorescent Proteins
Concept Mutant Proteins
Concept bcl-2 Homologous Antagonist-Killer Protein
Concept Apoptosis Regulatory Proteins
Concept bcl-2-Associated X Protein
Concept Amyloidogenic Proteins
Concept GPI-Linked Proteins
Concept Protein Aggregation, Pathological
Academic Article Molecular distinction between pathogenic and infectious properties of the prion protein.
Academic Article Post-transcriptional suppression of pathogenic prion protein expression in Drosophila neurons.
Academic Article Copper and zinc cause delivery of the prion protein from the plasma membrane to a subset of early endosomes and the Golgi.
Academic Article Cell surface expression of the prion protein in yeast does not alter copper utilization phenotypes.
Academic Article Mutational analysis of topological determinants in prion protein (PrP) and measurement of transmembrane and cytosolic PrP during prion infection.
Academic Article Trafficking, turnover and membrane topology of PrP.
Academic Article GFP-tagged prion protein is correctly localized and functionally active in the brains of transgenic mice.
Academic Article The neurotoxicity of prion protein (PrP) peptide 106-126 is independent of the expression level of PrP and is not mediated by abnormal PrP species.
Academic Article Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease.
Academic Article Cytosolic prion protein (PrP) is not toxic in N2a cells and primary neurons expressing pathogenic PrP mutations.
Academic Article Mammalian prion protein suppresses Bax-induced cell death in yeast.
Academic Article Visualization of prion infection in transgenic mice expressing green fluorescent protein-tagged prion protein.
Academic Article A transmembrane form of the prion protein is localized in the Golgi apparatus of neurons.
Academic Article Neurodegenerative illness in transgenic mice expressing a transmembrane form of the prion protein.
Academic Article New insights into prion structure and toxicity.
Academic Article Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125.
Academic Article N-terminally deleted forms of the prion protein activate both Bax-dependent and Bax-independent neurotoxic pathways.
Academic Article The cellular prion protein (PrP(C)): its physiological function and role in disease.
Academic Article Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice.
Academic Article Multiple biochemical similarities between infectious and non-infectious aggregates of a prion protein carrying an octapeptide insertion.
Academic Article Non-infectious aggregates of the prion protein react with several PrPSc-directed antibodies.
Academic Article Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans.
Academic Article Prion protein repeat expansion results in increased aggregation and reveals phenotypic variability.
Academic Article Doppel induces degeneration of cerebellar Purkinje cells independently of Bax.
Academic Article GFP-tagged mutant prion protein forms intra-axonal aggregates in transgenic mice.
Academic Article A deleted prion protein that is neurotoxic in vivo is localized normally in cultured cells.
Academic Article Aggregated, wild-type prion protein causes neurological dysfunction and synaptic abnormalities.
Academic Article Acute cellular uptake of abnormal prion protein is cell type and scrapie-strain independent.
Academic Article Prion protein lacks robust cytoprotective activity in cultured cells.
Academic Article Fishing for prion protein function.
Academic Article Prion neurotoxicity: insights from prion protein mutants.
Academic Article Mutant prion protein expression is associated with an alteration of the Rab GDP dissociation inhibitor alpha (GDI)/Rab11 pathway.
Academic Article Prion protein with an insertional mutation accumulates on axonal and dendritic plasmalemma and is associated with distinctive ultrastructural changes.
Academic Article Immunopurification of pathological prion protein aggregates.
Academic Article A novel, drug-based, cellular assay for the activity of neurotoxic mutants of the prion protein.
Academic Article A highly toxic cellular prion protein induces a novel, nonapoptotic form of neuronal death.
Academic Article Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells.
Academic Article A Drug-Based Cellular Assay (DBCA) for studying cytotoxic and cytoprotective activities of the prion protein: A practical guide.
Academic Article An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity.
Academic Article The N-terminal, polybasic region is critical for prion protein neuroprotective activity.
Academic Article A nine amino acid domain is essential for mutant prion protein toxicity.
Academic Article A naturally occurring C-terminal fragment of the prion protein (PrP) delays disease and acts as a dominant-negative inhibitor of PrPSc formation.
Academic Article Prion protein at the crossroads of physiology and disease.
Academic Article The toxicity of a mutant prion protein is cell-autonomous, and can be suppressed by wild-type prion protein on adjacent cells.
Academic Article Ion channels induced by the prion protein: mediators of neurotoxicity.
Academic Article Targeting the cellular prion protein to treat neurodegeneration.
Academic Article The N-terminal, polybasic region of PrP(C) dictates the efficiency of prion propagation by binding to PrP(Sc).
Academic Article An N-terminal fragment of the prion protein binds to amyloid-ß oligomers and inhibits their neurotoxicity in vivo.
Academic Article A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity.
Academic Article Brevin, a serum protein that acts on the barbed end of actin filaments.
Academic Article Differential activation of myotube nuclei following exposure to an acetylcholine receptor-inducing factor.
Academic Article A prion-like protein from chicken brain copurifies with an acetylcholine receptor-inducing activity.
Academic Article Studies on the mechanism of fast axoplasmic transport using microinjection into single giant neurons.
Academic Article Characterization of brevin, a serum protein that shortens actin filaments.
Academic Article Mr 42,000 ARIA: a protein that may regulate the accumulation of acetylcholine receptors at developing chick neuromuscular junctions.
Academic Article Glycolipid-anchored proteins in neuroblastoma cells form detergent-resistant complexes without caveolin.
Academic Article A glycolipid-anchored prion protein is endocytosed via clathrin-coated pits.
Academic Article Neurological illness in transgenic mice expressing a prion protein with an insertional mutation.
Academic Article Two mutant prion proteins expressed in cultured cells acquire biochemical properties reminiscent of the scrapie isoform.
Academic Article Identification of intermediate steps in the conversion of a mutant prion protein to a scrapie-like form in cultured cells.
Academic Article Evidence for a six-transmembrane domain structure of presenilin 1.
Academic Article Copper stimulates endocytosis of the prion protein.
Academic Article A wild-type prion protein does not acquire properties of the scrapie isoform when coexpressed with a mutant prion protein in cultured cells.
Academic Article The N-terminal domain of a glycolipid-anchored prion protein is essential for its endocytosis via clathrin-coated pits.
Academic Article Prion proteins carrying pathogenic mutations are resistant to phospholipase cleavage of their glycolipid anchors.
Academic Article Brain copper content and cuproenzyme activity do not vary with prion protein expression level.
Academic Article Cell biology of the prion protein.
Academic Article Mutant and infectious prion proteins display common biochemical properties in cultured cells.
Academic Article Cell-lysate conversion of prion protein into its protease-resistant isoform suggests the participation of a cellular chaperone.
Academic Article Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides.
Academic Article Processing of a cellular prion protein: identification of N- and C-terminal cleavage sites.
Academic Article A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells.
Academic Article Localization of the mRNA for a chicken prion protein by in situ hybridization.
Academic Article Sulfated glycans stimulate endocytosis of the cellular isoform of the prion protein, PrPC, in cultured cells.
Academic Article Blockade of glycosylation promotes acquisition of scrapie-like properties by the prion protein in cultured cells.
Academic Article A mutant prion protein displays an aberrant membrane association when expressed in cultured cells.
Academic Article Successful transmission of three mouse-adapted scrapie strains to murine neuroblastoma cell lines overexpressing wild-type mouse prion protein.
Academic Article Nerve growth factor-induced differentiation does not alter the biochemical properties of a mutant prion protein expressed in PC12 cells.
Academic Article A transgenic model of a familial prion disease.
Academic Article Prion diseases: what is the neurotoxic molecule?
Academic Article Accumulation of protease-resistant prion protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation.
Academic Article Mutant prion proteins are partially retained in the endoplasmic reticulum.
Academic Article PrP-dependent cell adhesion in N2a neuroblastoma cells.
Academic Article Biosynthesis and cellular processing of the prion protein.
Academic Article Cell biological studies of the prion protein.
Academic Article Most pathogenic mutations do not alter the membrane topology of the prion protein.
Academic Article Copper converts the cellular prion protein into a protease-resistant species that is distinct from the scrapie isoform.
Academic Article A transmembrane form of the prion protein contains an uncleaved signal peptide and is retained in the endoplasmic Reticulum.
Academic Article Primary myopathy and accumulation of PrPSc-like molecules in peripheral tissues of transgenic mice expressing a prion protein insertional mutation.
Academic Article Prion permissive pathways: extracellular matrix genes control susceptibility to prion infection.
Academic Article A C-terminal membrane anchor affects the interactions of prion proteins with lipid membranes.
Academic Article Mechanisms of prion-induced neurodegeneration.
Academic Article Identification of Anti-prion Compounds using a Novel Cellular Assay.
Academic Article A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells
Academic Article Molecular and Cellular Biology. Harris, D.A., (Ed.)
Academic Article A prion-like protein from chicken brain copurifies with an acetylcholine receptor-inducing activity
Academic Article Activation of zebrafish Src family kinases by the prion protein is an amyloid-ß-sensitive signal that prevents the endocytosis and degradation of E-cadherin/ß-catenin complexes in vivo.
Academic Article A Neuronal Culture System to Detect Prion Synaptotoxicity.
Academic Article Purification and characterization of muscle proteins from Aplysia californica
Academic Article Alzheimer’s Disease: Biology, Diagnosis and Therapeutics. Iqbal K, Winblad B, Nishimura T, Takeda M, Wisniewski HM (Eds)
Academic Article Localization of the mRNA for a chicken prion-like protein by in situ hybridization
Academic Article Prion Diseases and Copper Metabolism. Brown, DR (Ed)
Academic Article Advances in Protein Chemistry: Prion Proteins. Caughey, B. (Ed.)
Academic Article Handbook of Copper Pharmacology and Toxicology. Massaro EJ (Ed)
Academic Article GPI-Anchored Membrane Proteins and Carbohydrates. Hoessli, D.C., and Ilangumaran, S. (Eds.)
Academic Article The N-terminus of the prion protein is a toxic effector regulated by the C-terminus.
Academic Article Cellular prion protein targets amyloid-ß fibril ends via its C-terminal domain to prevent elongation.
Academic Article An inter-domain regulatory mechanism controls toxic activities of PrPC.
Academic Article Prions activate a p38 MAPK synaptotoxic signaling pathway.
Academic Article Prion neurotoxicity.
Academic Article Identification of anti-prion drugs and targets using toxicity-based assays.
Academic Article PrP-grafted antibodies bind certain amyloid ß-protein aggregates, but do not prevent toxicity.
Academic Article Altered Domain Structure of the Prion Protein Caused by Cu2+ Binding and Functionally Relevant Mutations: Analysis by Cross-Linking, MS/MS, and NMR.
Academic Article Intrinsic toxicity of the cellular prion protein is regulated by its conserved central region.
Academic Article Both N-Terminal and C-Terminal Histidine Residues of the Prion Protein Are Essential for Copper Coordination and Neuroprotective Self-Regulation.
Grant Discovering How Cu(II)/Zn(II) Uptake by the Prion Protein Controls Structure, Function and Neurotoxicity
Grant Mechanisms of Prion Protein Toxicity
Grant The Prion Protein as a Probe for Identifying Neurotoxic Protein Oligomers
Grant Targeting Prion Protein Pathways to Treat Alzheimer's Disease
Grant Ion Channel Modulation by the Prion Protein: A Novel Toxic Mechanism
Grant Prion Protein-Targeted Therapeutics for Alzheimer's Disease
Grant Molecular Aspects of Copper and Zinc Binding to the Prion Protein
Grant Treating Alzheimer's Disease with Prion Protein Ligands

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