Prions

Solid State

NMR spectroscopy of solid state has long been an important area of research in the Pines group. The development of capabilities in SSNMR in terms of instrumentation and high frequency magic-angle spinning methods, multi-dimensional dipolar recoupling pulse sequences, and sample preparation techniques have made SSNMR a promising technique for atomic-resolution structure determination of proteins involved in a wide range of disorders and human diseases.

Prions

Our recent work in high-resolution SSNMR includes a collaboration with the Wemmer and Prusiner labs to investigate the structures of synthetic mouse prion strains. In prion diseases or transmissible spongiform encephalopathies, an aberrantly folded conformer of the prion protein (PrPSc) propagates by catalyzing the post-translational misfolding of the cellular prion protein (PrPC). The aberrantly folded conformers often assemble into amyloid fibrils, which coalesce into plaques, characteristic of amyloid disease. Our collaborators in the Prusiner lab have recently succeeded in recapitulating this phenomenon in vitro by converting purified, bacterially-expressed, recombinant mouse PrP into an infectious state, which has now enabled us to begin deciphering the structural basis of prion protein-based infectivity at an atomic level.


Human Prion Protein Structure solved by Group Wuthrich
PNAS 97 (145) 2000
PDB 1QLX

One of the more remarkable aspects of prion biology is the strain phenomenon, whereby a single protein (PrPC) can misfold into multiple infectious states with distinguishable disease phenotypes (PrPSc), and these phenotypic differences are proposed to be encoded in the physical structure of PrPSc conformers. We will use multi-dimensional magic-angle spinning experiments to examine structural differences among different prion strains, in the attempt to "decipher the molecular language of prion strains". Elucidating the relationship between structure and neurological dysfunction will not only provide insights into the etiology of prion diseases such as Creutzfeldt-Jakob disease, but may illuminate the mechanism of neurodegeneration in more prevalent proteinopathies such as Alzheimer’s disease and Parkinson’s disease.