Alzheimer’s disease and Prion diseases

The Harris 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, the Harris lab’s work on prion and Alzheimer’s diseases will likely provide important insights into a number of other chronic, neurodegenerative disorders.

The lab’s work has two broad objectives. First, it wishes to understand how prions and other misfolded protein aggregates cause neurodegeneration, neuronal death and synaptic dysfunction.  In this regard, the Harris lab seeks 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, it aims 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.

The Harris lab utilizes a range of experimental systems and models, including transgenic mice, cultured mammalian cells, and in vitro systems. It employs 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.

Source:  http://www.bumc.bu.edu/biochemistry/people/faculty/david-a-harris/