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, Biochemistry, Boston University School of Medicine
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- Columbia University, MD
- Columbia University, PhD
- Yale University, BS
- Published on 11/2/2017
McDonald AJ, Wu B, Harris DA. An inter-domain regulatory mechanism controls toxic activities of PrPC. Prion. 2017 Nov 02; 11(6):388-397. PMID: 28960140.
- Published on 8/23/2017
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. PMID: 28842494.
- Published on 5/20/2017
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. PMID: 28527237.
- Published on 11/1/2016
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. PMID: 27803163.
- Published on 5/26/2016
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. PMID: 27227882.
- Published on 4/8/2016
Saá P, Harris DA, Cervenakova L. Mechanisms of prion-induced neurodegeneration. Expert Rev Mol Med. 2016 Apr 08; 18:e5. PMID: 27055367.
- Published on 2/9/2016
Sempou E, Biasini E, Pinzón-Olejua A, Harris DA, Málaga-Trillo E. Activation of zebrafish Src family kinases by the prion protein is an amyloid-ß-sensitive signal that prevents the endocytosis and degradation of E-cadherin/ß-catenin complexes in vivo. Mol Neurodegener. 2016 Feb 09; 11:18. PMID: 26860872.
- Published on 2/6/2016
Imberdis T, Harris DA. Synthetic Prions Provide Clues for Understanding Prion Diseases. Am J Pathol. 2016 Apr; 186(4):761-4. PMID: 26854642.
- Published on 9/12/2014
Chu NK, Shabbir W, Bove-Fenderson E, Araman C, Lemmens-Gruber R, Harris DA, Becker CF. A C-terminal membrane anchor affects the interactions of prion proteins with lipid membranes. J Biol Chem. 2014 Oct 24; 289(43):30144-60. PMID: 25217642.
- Published on 7/18/2014
Zeldich E, Chen CD, Colvin TA, Bove-Fenderson EA, Liang J, Tucker Zhou TB, Harris DA, Abraham CR. The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J Biol Chem. 2014 Aug 29; 289(35):24700-15. PMID: 25037225.
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