David A. Harris, MD, PhD
Professor and Chair, Department of Biochemistry
Location: 72 E. Concord Street, Silvio Conte Building, K225
Lab website: bumc.bu.edu/biochemistry/people/faculty/david-a-harris
Dr. Harris earned his B.S. degree at Yale University (New Haven, CT), and his M.D. and Ph.D. degrees at Columbia University (New York, NY). He was a faculty member in the Department of Cell Biology and Physiology at Washington University in St. Louis for 19 years before moving to Boston University School of Medicine in 2009 to assume the position of Professor and Chair in the Department of Biochemistry.
Dr. Harris’ 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, their work on prion and Alzheimer’s diseases will likely provide important insights into a number of other chronic, neurodegenerative disorders.
His lab’s work has several broad objectives. First, they wish to understand how the cellular form of the prion protein (PrPC) is converted into the infectious form (PrPSc). To address this question, they 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, they want to understand how prions and other misfolded protein aggregates cause neurodegeneration, neuronal death and synaptic dysfunction. In this regard, they seek to identify what molecular forms of PrP and the Alzheimer’s Aβ peptide represent the proximate neurotoxic species, and what receptors and cellular pathways they activate that lead to pathology. Third, they aim to use knowledge of the cell biology of prion and Alzheimer’s diseases to develop drug molecules for treatment of these disorders.
Dr. Harris’ lab utilizes a range of experimental systems and models, including transgenic mice, cultured mammalian cells, yeast (S. cerevisiae), and in vitro systems. They 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.
Dr. Harris serves a training faculty member for the NIA-funded Alzheimer’s Disease Translational Research Training Program (T32).
Fluharty, B.R., Biasini, E., Stravalaci, M., Sclip, A., Diomede, L., Balducci, C., La Vitola, P., Messa, M., Colombo, L., Forloni, G., Borsello, T., Gobbi, M., and D.A. Harris (2013). An N-terminal fragment of the prion protein binds to amyloid-β oligomers and inhibits their neurotoxicity in vivo. J. Biol. Chem. 288:7857-7866.
Biasini, E., Unterberger, U., Solomon, I.H., Massignan, T., Senatore, A., Bian, H., Voigtlaender, T., Bowman, F.P., Bonetto, V, Chiesa, R., Luebke, J., Toselli, P., and D.A. Harris (2013). A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity. J. Neurosci. 33:2408-2418.
Biasini E, Turnbaugh JA, Massignan T, Veglianese P, Forloni G, Bonetto V, Chiesa R, and Harris DA. The toxicity of a mutant prion protein is cell-autonomous, and can be suppressed by wild-type prion protein on adjacent cells. PLoS One 2012; 7(3): e33472. [PDF]
Turnbaugh JA, Unterberger U, Saá P, Massignan T, Fluharty BR, Bowman FP, Miller MB, Supattapone S, Biasini B, and Harris DA. The N-terminal, polybasic region of PrPC dictates the efficiency of prion propagation by binding to PrPSc. J Neurosci. 2012 Jun 27; 32(26): 8817-30. [PDF]
Biasini E and Harris DA. Targeting the cellular prion protein to treat neurodegeneration. Future Med Chem. 2012 Sep; 4(13): 1655-8. [Abstract]
Biasini E, Turnbaugh JA, Unterberger U, and Harris DA. Prion protein at the crossroads of physiology and disease. Trends Neurosci. 2012 Feb; 35(2): 92-103. [PDF]
Solomon IH, Khatri N, Biasini E, Massignan T, Huettner JE, and Harris DA. An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity. J Biol Chem. 2011 Apr 22; 286(16): 14724-36. [Full text]
Westergard L, Turnbaugh JA, and Harris DA. A nine amino acid domain is essential for mutant prion protein toxicity. J Neurosci. 2011 Sep 28; 31(39): 14005-17. [PDF]
Turnbaugh JA, Westergard L, Unterberger U, Biasini E, and Harris DA. The N-terminal, polybasic region is critical for prion protein neuroprotective activity. PLoS One 2011; 6(9): e25675. [PDF]
Westergard L, Turnbaugh JA, and Harris DA. A naturally occurring C-terminal fragment of the prion protein (PrP) delays disease and acts as a dominant-negative inhibitor of PrPSc formation. J Biol Chem. 2011 Dec 23; 286(51): 44234-42. [Full text]
Solomon IH, Huettner JE, and Harris DA. Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells. J Biol Chem. 2010 Aug 20; 285(34): 26719-26. [Full text]
Massignan T, Stewart RS, Biasini E, Solomon I, Bonetto V, Chiesa R, and Harris DA. A novel, drug-based cellular assay for the activity of neurotoxic mutants of the prion protein. J Biol Chem. 2010 Mar 5; 285(10): 7752-65. [Full Text]
Christensen HM, Dikranian K, Li A, Baysac KC, Walls KC, Olney JW, Roth KA, and Harris DA. A highly toxic cellular prion protein induces a novel, non-apoptotic form of neuronal death. Am J Pathol. 2010 Jun; 176(6): 2695-706. [PDF]
Chiesa R, and Harris DA. Fishing for prion protein function. PLoS Biology. 2009 Mar 31; 7(3): e75. [PDF]
Chiesa R, Piccardo P, Biasini E, Ghetti B, and Harris DA Aggregated, wild-type prion protein causes neurological dysfunction and synaptic abnormalities. J Neurosci. 2008 Dec 3; 28(49): 13258-67. [PDF]
Medrano AZ, Barmada SJ, Biasini E, and Harris DA GFP-tagged mutant prion protein forms intra-axonal aggregates in transgenic mice. Neurobiol Dis. 2008 Jul; 31(1): 20-32. [PDF]
Biasini E, Medrano AZ, Thellung S, Chiesa R, andHarris DA. Multiple biochemical similarities between infectious and non-infectious aggregates of a prion protein carrying an octapeptide insertion. J Neurochem. 2008 Mar; 104(5): 1293-308. [PDF]
Li A, Christensen HM, Stewart LR, Roth KA, Chiesa R, and Harris DA. Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125. EMBO J 2007 Jan 24;26(2):548-58. [PDF]
Harris DA, and True HL. New insights into prion structure and toxicity. Neuron 2006 May 4; 50(3): 353-7. [PDF]
Barmada SJ, and Harris DA . Visualization of prion infection in transgenic mice expressing GFP-tagged prion protein. J Neurosci. 2005 Jun 15; 25(24): 5824-32. [PDF]