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.
Cheng Fang – Instructor
Bei Wu – Instructor
Thibaut Imberdis – Postdoctoral Associate
Alex McDonald – Postdoctoral Associate
Erin Bove-Fenderson – Graduate Student
Celeste Rich – Staff
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.
Saá P, Harris DA, Cervenakova L. Mechanisms of prion-induced neurodegeneration. Expert Rev Mol Med. 2016; 18:e5. PMID: 27055367.
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; 11(1):18. PMID: 26860872.
Imberdis T, Harris DA. Synthetic Prions Provide Clues for Understanding Prion Diseases. Am J Pathol. 2016 Apr; 186(4):761-4. PMID: 26854642.
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.
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.
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.
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.
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.
Biasini E, Harris DA. Prions and Diseases (Volume 1). Zou, W.-Q. and Gambetti, P. (Eds.). Infectious and pathogenic forms of PrP. Springer Verlag. New York. 2013; 135-146.
Complete list can be found at BU Profiles