David A. Harris, MD, PhD
Professor
Boston University School of Medicine
Dept of Biochemistry

MD, Columbia University
PhD, Columbia University



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.

Chair of Biochemistry
Boston University School of Medicine
Biochemistry


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



1991-1994 Klingenstein Fellowship Award in the Neurosciences
1986-1991 National Institutes of Health: Clinical Investigator Development Award
1983 Columbia College of Physicians & Surgeons: Titus Munson Coan Prize
1983-1985 National Institutes of Health: Individual National Research Service Award
1983 Columbia College of Physicians & Surgeons: Frederick P. Gay Memorial Award
1981 Columbia College of Physicians & Surgeons: Alfred Steiner Research Award


Molecular Aspects of Copper and Zinc Binding to the Prion Protein
07/01/2015 - 06/30/2018 (PI)
The University of California, Santa Cruz NIH NIGMS
5R01GM065790-14

Identification of Anti-Prion Drug Targets
04/01/2017 - 03/31/2018 (PI)
NIH/National Institute of Neurological D
1R21NS101659-01

Mechanisms of Prion Protein Toxicity
03/01/2016 - 12/31/2017 (PI)
NIH/National Institute of Neurological D
5R01NS065244-07

Personnel Agreement for Research Services of Jamie Wilson
09/28/2015 - 09/27/2016 (PI)
Department of Veterans Administration, B

The Prion Protein as a Probe for Identifying Neurotoxic Protein Oligomers
09/22/2014 - 09/21/2016 (Co-PI)
PI: Erin Bove-Fenderson
NIH/National Institute of Neurological D
5F31NS090747-02

Treating Alzheimer's Disease with Prion Protein Ligands
07/01/2013 - 06/30/2016 (PI)
Bright Focus Foundation

Murine Transgenic Models of Prion Diseases
09/01/2011 - 05/31/2016 (PI)
NIH/National Institute of Neurological D
5R01NS040975-16

Ion Channel Modulation by the Prion Protein: A Novel Toxic Mechanism
07/01/2010 - 02/29/2016 (PI)
NIH/National Institute of Neurological D
5R01NS065244-05

Targeting Prion Protein Pathways to Treat Alzheimer's Disease
03/01/2014 - 02/28/2016 (PI)
Massachusetts Neuroscience Consortium

Prion Protein-Targeted Therapeutics for Alzheimer's Disease
12/31/2012 - 12/30/2014 (PI)
The Edward N. & Della L. Thome Memorial




Yr Title Project-Sub Proj Pubs
2017 Identification of Anti-Prion Drug Targets 1R21NS101659-01
2017 Mechanisms of Prion Protein Toxicity 5R01NS065244-07 14
2014 ION CHANNEL MODULATION BY THE PRION PROTEIN: A NOVEL TOXIC MECHANISM 5R01NS065244-05 14
2014 Murine Transgenic Models of Prion Diseases 5R01NS040975-15 39
2013 ION CHANNEL MODULATION BY THE PRION PROTEIN: A NOVEL TOXIC MECHANISM 5R01NS065244-04 14
2013 Murine Transgenic Models of Prion Diseases 5R01NS040975-14 39
2012 ION CHANNEL MODULATION BY THE PRION PROTEIN: A NOVEL TOXIC MECHANISM 5R01NS065244-03 14
2012 Murine Transgenic Models of Prion Diseases 5R01NS040975-13 39
2011 ION CHANNEL MODULATION BY THE PRION PROTEIN: A NOVEL TOXIC MECHANISM 3R01NS065244-01A2S1 14
2011 ION CHANNEL MODULATION BY THE PRION PROTEIN: A NOVEL TOXIC MECHANISM 5R01NS065244-02 14
Showing 10 of 72 results. Show All Results
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.

  1. 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 Aug 23.View Related Profiles. PMID: 28842494.
  2. 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 May 20; 6.View Related Profiles. PMID: 28527237.
  3. 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.
  4. 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.View Related Profiles. PMID: 27227882; PMCID: PMC4881977; DOI: 10.1371/journal.ppat.1005623;.
  5. Saá P, Harris DA, Cervenakova L. Mechanisms of prion-induced neurodegeneration. Expert Rev Mol Med. 2016 Apr 08; 18:e5. PMID: 27055367; DOI: 10.1017/erm.2016.8;.
  6. Sempou E, Biasini E, Pinzón-Olejua A, Harris DA, Málaga-Trillo E. 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. Mol Neurodegener. 2016 Feb 09; 11:18.View Related Profiles. PMID: 26860872; PMCID: PMC4748561; DOI: 10.1186/s13024-016-0076-5;.
  7. Imberdis T, Harris DA. Synthetic Prions Provide Clues for Understanding Prion Diseases. Am J Pathol. 2016 Apr; 186(4):761-4. PMID: 26854642; DOI: 10.1016/j.ajpath.2015.12.005;.
  8. Chu NK, Shabbir W, Bove-Fenderson E, Araman C, Lemmens-Gruber R, Harris DA, Becker CF. A C-terminal membrane anchor affects the interactions of prion proteins with lipid membranes. J Biol Chem. 2014 Oct 24; 289(43):30144-60.View Related Profiles. PMID: 25217642; PMCID: PMC4208020; DOI: 10.1074/jbc.M114.587345;.
  9. Zeldich E, Chen CD, Colvin TA, Bove-Fenderson EA, Liang J, Tucker Zhou TB, Harris DA, Abraham CR. The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J Biol Chem. 2014 Aug 29; 289(35):24700-15.View Related Profiles. PMID: 25037225; PMCID: PMC4148892; DOI: 10.1074/jbc.M114.567321;.
  10. Imberdis T, Harris DA. Prion permissive pathways: extracellular matrix genes control susceptibility to prion infection. EMBO J. 2014 Jul 17; 33(14):1506-8. PMID: 24952893; PMCID: PMC4198046; DOI: 10.15252/embj.201489071;.
Showing 10 of 83 results. Show More

This graph shows the total number of publications by year, by first, middle/unknown, or last author.

Bar chart showing 83 publications over 24 distinct years, with a maximum of 8 publications in 2007

YearPublications
19841
19891
19911
19932
19961
19971
19984
19993
20012
20022
20037
20045
20056
20061
20078
20086
20096
20104
20115
20124
20133
20143
20165
20172
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72 E. Concord St Silvio Conte (K)
Boston MA 02118
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