Prion Diseases

Some of the most devastating and intractable human diseases involve changes in protein conformation. One class of disease we study are the Transmissible Spongiform Encephalopathies (TSEs), a group of neurodegenerative diseases, commonly known as CJD in humans and "mad cow disease" in cattle. They are unique among infectious diseases in having infectious, spontaneous, and dominantly-heritable forms. For infectious disease, the transmissible agent (the prion) is composed mostly of a normal cellular plasma-membrane protein, PrPC, with an altered conformation, PrPSc. This conformation is central to the disease process. The widely accepted (but still controversial) "protein-only" hypothesis holds that PrPSc is itself infectious, interacting with normal PrPC molecules and inducing them to switch their conformations in a fatal chain reaction. We find that PrP expressed in the cytosol, instead of in the ER/secretory compartment, adapts the PrPSc conformation with high efficiency. We posit that PrPSc might originate from PrP proteins that misfold in the ER/secretory compartment and are targeted to the cytosol by retrograde transport.

HomeCageScan high-throughput analysis of mouse behavior. Mice are video-recorded while freely behaving in their home cages for 24-48 hours without experimenter interference. HCS software analyzes the positions of the mice and assigns behaviors, for example: (A) hang upside down; (B) groom; (C) eat; (D) drink (Courtesy of Andrew Steele).

Selected Publications on Prion Diseases

Chen D, Steele AD, Hutter G, Bruno J, Govindarajan A, Easlon E, Lin S-J, Aguzzi A, Lindquist S, Guarente L, 2008. The role of calorie restriction and SIRT1 in prion mediated neurodegeneration. Exp Gerontol, in press.

Steele AD, Hutter G, Jackson WS, Heppner FL, Borkowski AW, King OD, Raymond G, Aguzzi A, Lindquist S, 2008. Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease. Proc Natl Acad Sci USA, 105(36): 13626-13631. [PDF 1.7 MB]

Steele AD, Hetz C, Yi CH, Jackson WS, Borkowski AW, Yuan J, Wollmann RH, and Lindquist S, 2007. Prion Pathogenesis is Independent of Caspase-12. Prion 1(4):1-5. [PDF 416KB]

Steele AD, Lindquist S and Aguzzi A, 2007. The Prion Protein Knockout Mouse, A Phenotype Under Challenge. Prion 1(2): 83-93. [Review] [PDF 414 KB]

Steele AD, King OD, Jackson WS, Hetz CA, Borkowski AW, Thielen P, Wollmann R, and Lindquist S, 2007. Diminishing apoptosis by deletion of Bax or overexpression of Bcl-2 does not protect against infectious prion toxicity in vivo. J Neurosci 27(47):13022-13027. [PDF 320KB]

Steele AD, Jackson WS, King OD and Lindquist S, 2007. The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington's and prion diseases. Proc Natl Acad Sci USA 104(6): 1983-88.
[PDF 1.9 MB] [Supplementary Materials]

Steele AD, Emsley JG, Özdinler PH, Lindquist S, and Macklis JD, 2006. Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc Natl Acad Sci USA 103(9): 3416-21. [PDF 1.39 MB]

Zhang CC, Steele AD, Lindquist S and Lodish HF, 2006. Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc Natl Acad Sci USA 103(7): 2184-9. [PDF 378 KB]

Ma J and Lindquist S, 2002. Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol. Science 298:1779. [PDFLink]

Ma J, Wollmann R, and Lindquist S, 2002. Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298:1781. [PDFLink]

Ma J and Lindquist S, 2001. Wild-type PrP and a mutant associated with prion disease are subject to retrograde transport and proteasome degradation. Proc Natl Acad Sci USA98: 14955-14960. [PDF 584 KB]

Ma J and Lindquist S, 1999. De novo generation of a PrPSc-like conformation in living cells. Nat Cell Biol 1: 358-361.

Who's Working on Prion Diseases

Walker Jackson Artur Topolszki

Collaborators

Andy Steele, Caltech

Lenny Guarente, MIT

Alan Jasanoff, MIT

Harvey Lodish, WIBR

Jeff Macklis, Harvard

Yiqing Liang, Clever Systems, Inc.

Sculpture of PrP in the MIT museum, Spring 2008