David A. Harris, MD, PhD
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

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

Mechanisms of Prion Protein Toxicity
03/01/2016 - 12/31/2020 (PI)
NIH/National Institute of Neurological Disorders & Stroke

Genomic and Proteomic Analysis of Prion Synaptotoxicity
09/15/2018 - 08/31/2020 (PI)
NIH/National Institute of Neurological Disorders & Stroke

Molecular Aspects of Copper and Zinc Binding to the Prion Protein
07/01/2015 - 06/30/2019 (PI)
The University of California, Santa Cruz NIH NIGMS

Identification of Anti-Prion Drug Targets
04/01/2017 - 03/31/2019 (PI)
NIH/National Institute of Neurological Disorders & Stroke

Highly Synergistic Combination Therapy for Prion Diseases
01/09/2018 - 01/08/2019 (PI)
Creutzfeldt-Jakob Diseases Foundation, Inc.

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

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 Disorders & Stroke

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 Disorders & Stroke

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

Showing 10 of 12 results. Show All Results

Yr Title Project-Sub Proj Pubs
2019 Modeling prion diseases using human iPSC-derived neurons 1R21NS111499-01
2019 Mechanisms of Prion Protein Toxicity 5R01NS065244-09 26
2018 Genomic and Proteomic Analysis of Prion Synaptotoxicity 1R21NS107755-01A1
2018 Identification of Anti-Prion Drug Targets 5R21NS101659-02
2018 Mechanisms of Prion Protein Toxicity 5R01NS065244-08 26
2017 Identification of Anti-Prion Drug Targets 1R21NS101659-01
2017 Mechanisms of Prion Protein Toxicity 5R01NS065244-07 26
2016 Mechanisms of Prion Protein Toxicity 2R01NS065244-06A1 26
2015 Murine Transgenic Models of Prion Diseases 5R01NS040975-16 40
Showing 10 of 80 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. 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.View Related Profiles. PMID: 30956132.
  2. Mercer RC, Harris DA. Identification of anti-prion drugs and targets using toxicity-based assays. Curr Opin Pharmacol. 2019 Feb; 44:20-27. PMID: 30684854.
  3. Le NTT, Wu B, Harris DA. Prion neurotoxicity. Brain Pathol. 2019 03; 29(2):263-277.View Related Profiles. PMID: 30588688.
  4. 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.
  5. 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.View Related Profiles. PMID: 30235355.
  6. McDonald AJ, Wu B, Harris DA. An inter-domain regulatory mechanism controls toxic activities of PrPC. Prion. 2017 11 02; 11(6):388-397.View Related Profiles. PMID: 28960140.
  7. 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.View Related Profiles. PMID: 28842494.
  8. 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.View Related Profiles. PMID: 28527237.
  9. 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.View Related Profiles. PMID: 27803163.
  10. 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;.
Showing 10 of 135 results. Show More

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

Bar chart showing 135 publications over 35 distinct years, with a maximum of 9 publications in 2001

In addition to these self-described keywords below, a list of MeSH based concepts is available here.

Prion Diseases
Alzheimer's Disease
Contact for Mentoring:

Prion Disease Harms Neurons via Stress Pathway

Genetic Engineering & Biotechnology News 9/24/2018

72 E. Concord St Silvio Conte (K)
Boston MA 02118
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