David A. Harris
Boston University School of Medicine
Silvio Conte Building, K225
72 E. Concord Street
Boston, MA. 02118
Silvio Conte Building, K225
72 E. Concord Street
Boston, MA. 02118
Lab Phone: 617-638-4117
BS, Yale University, New Haven, CT
MD, PhD, Columbia University, New York, NY
Alzheimer’s disease and Prion diseases
My laboratory investigates the molecular and cellular mechanisms underlying two classes of human neurodegenerative disorders: Alzheimer’s and prion diseases. 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 two broad objectives. First, we wish 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 Aβ peptide represent the proximate neurotoxic species, and what receptors and cellular pathways they activate that lead to pathology. Second, we aim to use our knowledge of the cell biology of prion and Alzheimer’s diseases to develop drug molecules and other therapeutic modalities for treatment of these disorders.
We utilize a range of experimental systems and models, including transgenic mice, cultured mammalian cells, 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, field recordings), medicinal chemistry, and drug discovery approaches.
- 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, J.A., Massignan, T., Veglianese, P., Forloni, G., Bonetto, V., Chiesa, R., and D.A. Harris (2012). The toxicity of a mutant prion protein is cell-autonomous, and can be suppressed by wild-type prion protein on adjacent cells. PLoS One 7:e33472.
- Turnbaugh, J.A., Unterberger, U., Saá, P., Massignan, T., Fluharty, B.R., Bowman, F.P., Miller, M.B., Supattapone, S., Biasini, B., and D.A. Harris (2012). The N-terminal, polybasic region of PrPC dictates the efficiency of prion propagation by binding to PrPSc. J. Neurosci. 32:8817– 8830.
- Biasini, E., and D.A. Harris (2012). Targeting the cellular prion protein to treat neurodegeneration. Future Med. Chem. 4:1655–1658.
- Biasini, E., Turnbaugh, J.A., Unterberger, U., and D.A. Harris (2012). Prion protein at the crossroads of physiology and disease. Trends Neurosci. 35:92-103.
- Solomon, I.H., Khatri, N., Biasini E., Massignan T., Huettner J.E., and D.A. Harris (2011). An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity. J. Biol. Chem. 286:14724-14736.
- Westergard, L., Turnbaugh, J.A., and D.A. Harris (2011). A nine amino acid domain is essential for mutant prion protein toxicity. J. Neurosci. 31:14005-14017.
- Turnbaugh, J.A., Westergard, L., Unterberger, U., Biasini, E., and D.A. Harris (2011). The N-terminal, polybasic region is critical for prion protein neuroprotective activity. PLoS One 6:e25675.
- Westergard, L., Turnbaugh, J.A., and D.A. Harris (2011). 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. 286:44234-44242.
- Solomon, I.H., Huettner, J.E., and D.A. Harris (2010). Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells. J. Biol. Chem. 285:26719–26726.
- Massignan, T., Stewart, R.S., Biasini, E., Solomon, I., Bonetto, V., Chiesa, R., and D.A. Harris (2010). A novel, drug-based cellular assay for the activity of neurotoxic mutants of the prion protein. J. Biol. Chem. 285:7752–7765.
- Christensen, H.M., Dikranian, K., Li, A., Baysac, K.C., Walls, K.C., Olney, J.W., Roth, K.A., and D.A. Harris (2010). A highly toxic cellular prion protein induces a novel, non-apoptotic form of neuronal death. Am. J. Path. 176:2695-2706.
- Jeffrey, M., Goodsir, C., McGovern, G., Barmada, S.J., Medrano, A.Z., and D.A. Harris (2009). Prion protein with an insertional mutation accumulates on axonal and dendritic plasmalemma, and is associated with distinctive ultrastructural changes. Am. J. Path. 175:1208-1217.
- Christensen, H.M., and D.A. Harris (2009). A deleted prion protein that is neurotoxic in vivo is localized normally in cultured cells. J. Neurochem. 108:44-56.
- Chiesa, R., and D.A. Harris (2009). Fishing for prion protein function. PLoS Biology. 7:e1000075.
- Chiesa, R., Piccardo, P., Biasini, E., Ghetti, B., and D.A. Harris (2008). Aggregated, wild-type prion protein causes neurological dysfunction and synaptic abnormalities. J. Neurosci. 28:13258-13267.
- Medrano, A.Z., Barmada, S.J., Biasini, E., and D.A. Harris (2008). GFP-tagged mutant prion protein forms intra-axonal aggregates in transgenic mice. Neurobiol. Disease. 31:20-32.
- Biasini, E., Medrano, A.Z., Thellung, S., Chiesa, R., and D.A. Harris (2008). Multiple biochemical similarities between infectious and non-infectious aggregates of a prion protein carrying an octapeptide insertion. J. Neurochem. 104:1293-1308.
- Li, A., Christensen, H.M., Stewart, L.R., Roth, K.A., Chiesa, R., and D.A. Harris (2007). Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125. EMBO J. 26:548-558.
- Harris, D.A., and H.L. True (2006). New insights into prion structure and toxicity. Neuron. 50:353-357.
- Barmada, S.J., and D.A. Harris (2005). Visualization of prion infection in transgenic mice expressing GFP-tagged prion protein. J. Neurosci. 25(24):5824-5832.