David A. Harris, MD, PhD

Chair of Biochemistry, Boston University Chobanian & Avedisian School of Medicine

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.

Publications

  • Published 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 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 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 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 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

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

Education

  • Columbia University, MD
  • Columbia University, PhD
  • Yale University, BS