David A. Harris, MD, PhD
Chair of Biochemistry, Biochemistry & Cell Biology
Biography
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.
Other Positions
- Edgar Minas Housepian, MD Professor, Biochemistry & Cell Biology, Boston University Chobanian & Avedisian School of Medicine
- Member, Evans Center for Interdisciplinary Biomedical Research, Boston University
- Member, Genome Science Institute, Boston University
- Graduate Faculty (Primary Mentor of Grad Students), Boston University Chobanian & Avedisian School of Medicine, Graduate Medical Sciences
Websites
Education
- Columbia University, MD
- Columbia University, PhD
- Yale University, BS
Publications
- Published on 9/26/2024
Gojanovich AD, Le NTT, Mercer RCC, Park S, Wu B, Anane A, Vultaggio JS, Mostoslavsky G, Harris DA. Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease. Stem Cell Reports. 2024 Oct 08; 19(10):1474-1488. PMID: 39332406.
Read at: PubMed - Published on 5/14/2024
Mercer RCC, Le NTT, Fraser DG, Houser MCQ, Beeler AB, Harris DA. Sigma Receptor Ligands Are Potent Antiprion Compounds that Act Independently of Sigma Receptor Binding. ACS Chem Neurosci. 2024 Jun 05; 15(11):2265-2282. PMID: 38743607.
Read at: PubMed - Published on 11/29/2023
Mercer RCC, Le NTT, Houser MCQ, Beeler AB, Harris DA. Sigma receptor ligands are potent anti-prion compounds that act independently of sigma receptor binding. bioRxiv. 2023 Nov 29. PMID: 38077011.
Read at: PubMed - Published on 7/27/2023
Schilling KM, Jorwal P, Ubilla-Rodriguez NC, Assafa TE, Gatdula JRP, Vultaggio JS, Harris DA, Millhauser GL. N-glycosylation is a potent regulator of prion protein neurotoxicity. J Biol Chem. 2023 Sep; 299(9):105101. PMID: 37507020.
Read at: PubMed - Published on 9/7/2022
Mercer RCC, Harris DA. Mechanisms of prion-induced toxicity. Cell Tissue Res. 2023 Apr; 392(1):81-96. PMID: 36070155.
Read at: PubMed - Published on 2/19/2022
Shafiq M, Da Vela S, Amin L, Younas N, Harris DA, Zerr I, Altmeppen HC, Svergun D, Glatzel M. The prion protein and its ligands: Insights into structure-function relationships. Biochim Biophys Acta Mol Cell Res. 2022 06; 1869(6):119240. PMID: 35192891.
Read at: PubMed - Published on 11/24/2021
Linsenmeier L, Mohammadi B, Shafiq M, Frontzek K, Bär J, Shrivastava AN, Damme M, Song F, Schwarz A, Da Vela S, Massignan T, Jung S, Correia A, Schmitz M, Puig B, Hornemann S, Zerr I, Tatzelt J, Biasini E, Saftig P, Schweizer M, Svergun D, Amin L, Mazzola F, Varani L, Thapa S, Gilch S, Schätzl H, Harris DA, Triller A, Mikhaylova M, Aguzzi A, Altmeppen HC, Glatzel M. Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies. Sci Adv. 2021 Nov 26; 7(48):eabj1826. PMID: 34818048.
Read at: PubMed - Published on 6/8/2021
Amin L, Harris DA. Aß receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers. Nat Commun. 2021 06 08; 12(1):3451. PMID: 34103486.
Read at: PubMed - Published on 11/26/2020
Kim SY, Zhang F, Harris DA, Linhardt RJ. Structural Features of Heparin and Its Interactions With Cellular Prion Protein Measured by Surface Plasmon Resonance. Front Mol Biosci. 2020; 7:594497. PMID: 33324681.
Read at: PubMed - Published on 5/28/2020
Schilling KM, Tao L, Wu B, Kiblen JTM, Ubilla-Rodriguez NC, Pushie MJ, Britt RD, Roseman GP, Harris DA, Millhauser GL. Both N-Terminal and C-Terminal Histidine Residues of the Prion Protein Are Essential for Copper Coordination and Neuroprotective Self-Regulation. J Mol Biol. 2020 07 24; 432(16):4408-4425. PMID: 32473880.
Read at: PubMed
View 137 more publications: View full profile at BUMC