Prion diseases are fatal neurodegenerative disorders caused by an aggregated form of the prion protein, PrPSc. Prions are the only protein aggregates that are naturally transmitted as an infectious disease, and most recently, human to human transmission likely occurred by transfusion of prion-contaminated blood. Most cases of natural transmission occur through a peripheral exposure followed by prion spread to the CNS. Although prions are thought to spread via peripheral nerves to the CNS, the molecular mechanisms underlying neuronal transit are unclear. For this reason, a major goal of this grant application is to understand how prion aggregates spread to the CNS. We hypothesize that prions propagate by retrograde axonal transport and will address this hypothesis using in vitro and in vivo experimental models. To accomplish this goal, three aims are proposed. In the first aim, we will test the mechanism of PrPSc axonal transport using compartmentalized neuronal cultures that have a liquid separation between the axon terminals and the cell bodies. We will additionally assess the peripheral nerve transport of prion strains in vivo. In the second aim, we will measure the structural properties of the highly virulent prion strains that readily spread to he CNS. In the third aim, we will determine the role of the GPI membrane anchor of PrPC on prion spread to the brain using transgenic mice and primary neurons that express PrPC possessing or lacking the GPI anchor. We expect that these studies will provide critical missing information on the basic mechanisms of prion spread that will be essential for the development of immunotherapies and novel therapeutic strategies to prevent or arrest disease progression.

Public Health Relevance

Prion infections are caused by misfolded proteins that invade the nervous system and ultimately lead to progressive deterioration and death. In most cases, prion infections are transmitted by foodborne contamination and are thought to spread through nerves into the brain. We propose to investigate the underlying mechanisms for how prions spread to the brain in order to develop new strategies to block prion propagation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076896-02
Application #
8542907
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wong, May
Project Start
2012-09-15
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$327,523
Indirect Cost
$107,108
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Joshi-Barr, Shivanjali; Bett, Cyrus; Chiang, Wei-Chieh et al. (2014) De novo prion aggregates trigger autophagy in skeletal muscle. J Virol 88:2071-82
Kurt, Timothy D; Bett, Cyrus; Fernández-Borges, Natalia et al. (2014) Prion transmission prevented by modifying the ?2-?2 loop structure of host PrPC. J Neurosci 34:1022-7
Kurt, Timothy D; Jiang, Lin; Bett, Cyrus et al. (2014) A proposed mechanism for the promotion of prion conversion involving a strictly conserved tyrosine residue in the ?2-?2 loop of PrPC. J Biol Chem 289:10660-7
Bett, Cyrus; Kurt, Tim D; Lucero, Melanie et al. (2013) Defining the conformational features of anchorless, poorly neuroinvasive prions. PLoS Pathog 9:e1003280