David A. Harris

Harris Lab- Dec 12th 2011- BProfessor
Chair, Department of Biochemistry

Boston University School of Medicine
Silvio Conte Building, K225
72 E. Concord Street
Boston, MA. 02118

Phone: 617-638-4362
Lab Phone: 617-638-4117
Fax: 617-638-5339
Email: daharris@bu.edu

Education

BS, Yale University, New Haven, CT
MD, PhD, Columbia University, New York, NY

People

Emiliano Biasini
Instructor		 Tania Massignan
Postdoctoral Fellow		  Natasha Khatri
Graduate Student
Rick Bowman
Staff		 Jessie Turnbaugh
Postdoctoral Fellow		 Brian Fluharty
Graduate Student
     

POSTDOCTORAL POSITION – ION CHANNEL PHYSIOLOGY

 A postdoctoral position is available in the Harris laboratory to study the role of ion channel abnormalities in neurodegenerative diseases, particularly Alzheimer’s and prion diseases.  Candidates should hold a Ph.D. and/or M.D. degree, or the equivalent, and have experience in electrophysiological techniques, including patch-clamp recording and LTP measurements.  Please send a curriculum vitae, statement of research interests, and the names of three references to: daharris@bu.edu

 

Research Interests

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. Prion diseases 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. Prions also 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 diseases share important similarities with a larger group of neurodegenerative disorders, including Alzheimer’s, Huntington’s and Parkinson’s diseases, that are due to protein misfolding and aggregation.  A prion-like process may be responsible for the spread of brain pathology in these other disorders, and there is evidence that the prion protein itself may mediate the neurotoxic effects of multiple kinds of misfolded protein.

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 investigate 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.  For example, we seek to identify what molecular forms of PrP represent the proximate neurotoxic species, and what cellular pathways they activate that lead to pathology.  Third, we aim to use our knowledge of the cell biology of prion diseases to develop therapeutic strategies for preventing generation of PrPSc and inhibiting its toxic effects.  Finally, in a new line of investigation, we are exploring the role of PrPC as a cell-surface receptor for the Aβ peptide that causes Alzheimer’s disease.  These studies promise to provide mechanistic insight into both prion and Alzheimer’s disease, and may lead to the development of therapeutic agents for treatment of both kinds of illness.

We utilize a range of experimental systems, from transgenic mice, to cultured mammalian cells, to yeast (S. cerevisiae). We employ a wide variety of techniques, including protein chemistry, immunofluorescence and GFP-based cell labeling, light and electron microscopy, DNA microarrays, mouse transgenetics, neuropathology, animal bioassays, biophysical techniques (surface plasmon resonance, NMR), and electrophysiology (patch-clamping).

Research Themes

Neuroscience & Aging

 

Representative Publications

  • 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.
  • 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.