Prion protein in health and disease

The prion protein (PrP) is a conserved glycoprotein tethered to cell membranes by a glycosylphosphatidylinositol anchor. In mammals, PrP is expressed in many tissues, most abundantly in brain, heart, and muscle. Importantly, PrP is required for prion diseases, which are neurodegenerative diseases associated with misfolding and aggregation of PrP. PrP can adopt a self-perpetuating conformation that templates the misfolding of normal PrP molecules into its pathogenic conformation, termed PrPsC. The role of PrPSC in the pathogenesis of prion diseases, or transmissible spongiform encephalopathies, has been studied intensively yet the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Much less attention has been focused on the role of PrP in normal physiology despite the possibility that deciphering PrP's normal function could help to understand prion diseases. My thesis work has spanned both the study of the normal function of PrP and the neurotoxic pathways that are involved in prion pathogenesis. Because prion disease and other neurodegenerative diseases share protein misfolding as the primary etiology, I aimed to determine whether PrP contributed to other neurodegenerative diseases apart from prion diseases. We deleted PrP from several well established transgenic mouse models of neurodegenerative disease, including Tauopathy, Parkinson's and Huntington's diseases. Deleting PrP did not substantially alter the disease phenotypes of the models that we tested, suggesting that PrP is not a major contributor to or protector against these disorders. In addition, in collaborative efforts we determined that PrP knockout mice have defects in hematopoiesis and neurogenesis.

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Biology

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2008

Author dc:creator

• Steele, Andrew D.

Advisor dc:contributor.advisor

• Susan L. Lindquist.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/42396

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/42396