Prions: structure, strains, and spontaneous disease
One key interest lies in understanding how the structure of the prion aggregate impacts the brain regions and organs that are targeted in disease. Prion proteins that have the same amino acid sequence can assemble into different structures, or strains, which lead to distinct disease phenotypes. We have propagated strains that form dense plaques composed of long fibrils, and other strains that form diffuse aggregates. These two strain types target specific neurons in the brain and lead to different clinical signs. Certain prion strains are not able to enter the brain from extraneural sites but continue to accumulate in the spleen and lymph nodes. Current studies are underway to define the underlying mechanisms and structural properties that enable or block prion entry into the central nervous system.


Distinct prion strains stained with Congo red. Prion aggregates expand the blood vessel wall (V) and extend into the brain parenchyma. Electron micrograph of a fibrillar prion shows fibrils radiating outward from a central core.
Distinct prion strains stained with Congo red.   Prion aggregates expand the blood vessel wall and extend into the brain parenchyma   Electron micrograph of a fibrillar prion shows fibrils radiating outward from a central core.
Globular domain of the prion protein with the β2-α2 loop region shown in red.
The molecular mechanisms that underlie prion aggregation, transmission between species, and prion strain differences are still poorly understood. Therefore another research focus is to identify the key residues of the prion protein that govern species barriers and strain conformation. The β2-α2 loop of the prion protein (amino acids 165-175) is a site of exceptionally high sequence variability. Microcrystallography experiments have revealed that adjacent β2-α2 loops can align as β-sheets with side chains that intermesh in a dry interface as part of the amyloid core. We have shown that two amino acid substitutions in the β2-α2 loop of the mouse prion protein lead to de novo prion disease in transgenic mice. In addition, we have found that these substitutions markedly change interspecies transmission barriers. We are now determining the role of critical residues for conformational conversion in order to resolve the fundamental underpinnings of prion protein aggregation and cross-species transmission. We also work with structural biologists toward the rationale design of therapeutics to block prion aggregation.