My laboratory investigates the molecular and cellular mechanisms underlying two classes of human neurodegenerative disorders: prion and Alzheimer’s 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.
Our work has two broad objectives. First, we wish 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 Aβ peptide represent the proximate neurotoxic species, and what receptors and cellular pathways they activate that lead to pathology. Second, we aim 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.
Ladan Amin – Postdoctoral Associate
Nhat Le – Postdoctoral Associate
Robert Mercer – Postdoctoral Associate
- McDonald AJ, Leon DR, Markham KA, Wu B, Heckendorf CF, Schilling K, Showalter HD, Andrews PC, McComb ME, Pushie MJ, Costello CE, Millhauser GL, Harris DA. Altered Domain Structure of the Prion Protein Caused by Cu2+ Binding and Functionally Relevant Mutations: Analysis by Cross-Linking, MS/MS, and NMR. Structure. 2019 06 04; 27(6):907-922.e5. PMID:30956132
- Mercer RC, Harris DA. Identification of anti-prion drugs and targets using toxicity-based assays. Curr Opin Pharmacol. 2019 02; 44:20-27. PMID: 30684854
- Le NTT, Wu B, Harris DA. Prion neurotoxicity. Brain Pathol. 2019 03; 29(2):263-277. PMID: 30588688
- Mengel D, Hong W, Corbett GT, Liu W, DeSousa A, Solforosi L, Fang C, Frosch MP, Collinge J, Harris DA, Walsh DM. PrP-grafted antibodies bind certain amyloid ß-protein aggregates, but do not prevent toxicity. Brain Res. 2019 May 01; 1710:125-135. PMID: 30593771
- Fang C, Wu B, Le NTT, Imberdis T, Mercer RCC, Harris DA. Prions activate a p38 MAPK synaptotoxic signaling pathway. PLoS Pathog. 2018 09; 14(9):e1007283. PMID: 30235355
- McDonald AJ, Wu B, Harris DA. An inter-domain regulatory mechanism controls toxic activities of PrPC. Prion. 2017 11 02; 11(6):388-397. PMID: 28960140
- 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
- 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
- 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
- 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
Complete list can be found at BU Profiles