Project 2 Stubbs Many neurodegenerative diseases are associated with amyloid deposits, aggregates of misfolded proteins characterized by -strands extending roughly perpendicular to the axes of long, unbranched fibrils. Examples include Alzheimer's disease associated with the peptide A, Parkinson's disease associated with the protein ?-synuclein, a number of diseases including Alzheimer's and chronic traumatic encephalopathy associated with the protein tau, and Creuzfeldt-Jakob and others associated with the mammalian prion protein PrP. These diseases have in common the property of self-propagation of the aberrant peptide fold, as originally recognized in the mammalian prions derived from PrP. The structural and self-propagating properties of the amyloid form of PrP are shared by other pathological amyloids, and these diseases are essentially all prion diseases. Molecular structure and structural transitions are thus the key to understanding these diseases, and eventually to designing diagnostic and therapeutic interventions. Knowledge of the amyloid structure will provide information about the precursor oligomers that have in many cases been identified as the toxic species, and share structural features with the fibrils. Knowledge of the amyloid structure combined with information about the oligomers (Projects 3, 4) will also increase understanding of the interconversion pathways that include the toxic species. The overall goal of this project is to determine the structures of amyloids associated with some of the most devastating neurodegenerative diseases. Amyloids are not conducive to crystallographic or solution NMR studies, so the primary approaches are fiber diffraction and cryo-electron microscopy, well suited to relatively disordered filamentous assemblies such as amyloids. Model restraints will also come from other methods.
The specific aims address A, tau, and PrP. Structural and biological differences between synthetic and brain- derived A have been identified but not yet characterized. Tau and PrP studies will address the minimal requirement for a self-propagating amyloid. Sample assays for self-propagation in vivo will be correlated with the structural studies.
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| Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) Familial Parkinson's point mutation abolishes multiple system atrophy prion replication. Proc Natl Acad Sci U S A 115:409-414 |
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