David A. Harris, MD, PhD

Professor, Biochemistry

David Harris
617.358.4280
72 E. Concord St Silvio Conte (K)

Biography

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.

Other Positions

  • Chair, Biochemistry, Boston University School of Medicine
  • Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Graduate Medical Sciences

Education

  • Columbia University, MD
  • Columbia University, PhD
  • Yale University, BS

Publications

  • Published on 4/4/2019

    McDonald AJ, Leon DR, Markham KA, Wu B, Heckendorf CF, Schilling K, Showalter HD, Andrews PC, McComb ME, Pushie MJ, Costello CE, Millhauser GL, Harris DA. Altered Domain Structure of the Prion Protein Caused by Cu2+ Binding and Functionally Relevant Mutations: Analysis by Cross-Linking, MS/MS, and NMR. Structure. 2019 Jun 04; 27(6):907-922.e5. PMID: 30956132.

    Read at: PubMed
  • Published on 1/23/2019

    Mercer RC, Harris DA. Identification of anti-prion drugs and targets using toxicity-based assays. Curr Opin Pharmacol. 2019 Jan 23; 44:20-27. PMID: 30684854.

    Read at: PubMed
  • Published on 1/17/2019

    Le NTT, Wu B, Harris DA. Prion neurotoxicity. Brain Pathol. 2019 03; 29(2):263-277. PMID: 30588688.

    Read at: PubMed
  • Published on 12/26/2018

    Mengel D, Hong W, Corbett GT, Liu W, DeSousa A, Solforosi L, Fang C, Frosch MP, Collinge J, Harris DA, Walsh DM. PrP-grafted antibodies bind certain amyloid ß-protein aggregates, but do not prevent toxicity. Brain Res. 2019 May 01; 1710:125-135. PMID: 30593771.

    Read at: PubMed
  • Published on 9/20/2018

    Fang C, Wu B, Le NTT, Imberdis T, Mercer RCC, Harris DA. Prions activate a p38 MAPK synaptotoxic signaling pathway. PLoS Pathog. 2018 09; 14(9):e1007283. PMID: 30235355.

    Read at: PubMed
  • Published on 11/2/2017

    McDonald AJ, Wu B, Harris DA. An inter-domain regulatory mechanism controls toxic activities of PrPC. Prion. 2017 11 02; 11(6):388-397. PMID: 28960140.

    Read at: PubMed
  • Published on 8/23/2017

    Bove-Fenderson E, Urano R, Straub JE, Harris DA. Cellular prion protein targets amyloid-ß fibril ends via its C-terminal domain to prevent elongation. J Biol Chem. 2017 Oct 13; 292(41):16858-16871. PMID: 28842494.

    Read at: PubMed
  • Published on 5/20/2017

    Wu B, McDonald AJ, Markham K, Rich CB, McHugh KP, Tatzelt J, Colby DW, Millhauser GL, Harris DA. The N-terminus of the prion protein is a toxic effector regulated by the C-terminus. Elife. 2017 05 20; 6. PMID: 28527237.

    Read at: PubMed
  • Published on 11/1/2016

    Imberdis T, Heeres JT, Yueh H, Fang C, Zhen J, Rich CB, Glicksman M, Beeler AB, Harris DA. Identification of Anti-prion Compounds using a Novel Cellular Assay. J Biol Chem. 2016 Dec 09; 291(50):26164-26176. PMID: 27803163.

    Read at: PubMed
  • Published on 5/26/2016

    Fang C, Imberdis T, Garza MC, Wille H, Harris DA. A Neuronal Culture System to Detect Prion Synaptotoxicity. PLoS Pathog. 2016 May; 12(5):e1005623. PMID: 27227882.

    Read at: PubMed

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