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
- Brain Pathol. 2019 Mar;29(2):263-277. doi: 10.1111/bpa.12694. Epub 2019 Jan 17. PubMed PMID: 30588688.
- McDonald, A.J., Leon, D.R., Markham, K.A., Wu, B., Heckendorf, C.F., Schilling, K., Showalter, H.D., Andrews, P.C., McComb, M.E., Pushie, J., Costello, C.E., Millhauser, G.L., and D.A. Harris (2019). Altered domain structure of the prion protein caused by Cu2+ binding and functionally relevant mutations: analysis by cross-linking, MS/MS, and NMR. Structure. 27:1-16.
- Mercer, R.C.C., and D.A. Harris (2019) Identification of anti-prion drugs and targets using toxicity-based assays. Curr. Op. Pharm. 44:20-27. PMID: 30684854
- Fang, C., Wu, B., Le, N.T.T., Imberdis, T., Mercer, R.C.C., D.A. Harris (2018) Prions activate a p38 MAPK synaptotoxic signaling pathway. PLoS Pathogens 14(9): e1007283. PMID: 30235355
- McDonald AJ, Wu B, Harris DA. An Inter-Domain Regulatory Mechanism Controls Toxic Activities of PrPC. Prion. 2017 Sep 29; 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 Aug 23. 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 May 20; 6. PMID: 28527237.
Imberdis T, Heeres JT, Yueh H, Fang C, Zhen J, Rich CB, Glicksman M, Beeler A, Harris DA. Identification of Anti-Prion Compounds Using a Novel Cellular Assay. J Biol Chem. 2016 Nov 1. PMID: 27803163.
View in: PubMed
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.
View in: PubMed
Saá P, Harris DA, Cervenakova L. Mechanisms of prion-induced neurodegeneration. Expert Rev Mol Med. 2016 Apr 08; 18:e5. PMID: 27055367. View in: PubMed
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. View in: PubMed
Imberdis T, Harris DA. Synthetic Prions Provide Clues for Understanding Prion Diseases. Am J Pathol. 2016 Apr; 186(4):761-4. PMID: 26854642. View in: PubMed
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.View in: PubMed
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. View in: PubMed
Imberdis T, Harris DA. Prion permissive pathways: extracellular matrix genes control susceptibility to prion infection. EMBO J. 2014 Jul 17; 33(14):1506-8. PMID: 24952893. View in: PubMed
Biasini E, Unterberger U, Solomon IH, Massignan T, Senatore A, Bian H, Voigtlaender T, Bowman FP, Bonetto V, Chiesa R, Luebke J, Toselli P, Harris DA. A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity. J Neurosci. 2013 Feb 6; 33(6):2408-18. PMID: 23392670. View in: PubMed
Fluharty BR, Biasini E, Stravalaci M, Sclip A, Diomede L, Balducci C, La Vitola P, Messa M, Colombo L, Forloni G, Borsello T, Gobbi M, Harris DA. An N-terminal fragment of the prion protein binds to amyloid-ß oligomers and inhibits their neurotoxicity in vivo. J Biol Chem. 2013 Mar 15; 288(11):7857-66. PMID: 23362282.
Complete list can be found at BU Profiles