Three major advances have been made during the last four years of AG10770 funding: First, the Neuropathology Research Laboratory (NRL) verified that recombinant MoPrP(89-230) folded into amyloid filaments are prions because they caused a neurodegenerative disease with the neuropathological features of prion disease and because the disease could be serially transmitted. Moreover, the neuropathological phenotype indicated that the synthetic prions were a new prion strain. Second, the NRL found that neurodegeneration caused by natural prion strains proceeds in a stereotypical sequence that begins with accumulation of PrPSc in presynaptic boutons, is followed within two weeks by synaptic dysfunction, degeneration of boutons, and dendritic atrophy, and finally results in nerve cell death one to two months later. For the past two years, we focused on early-occurring synaptic degeneration because it is potentially reversible and, therefore, relevant to drug therapies for prion diseases. Third, we applied discoveries of developmental neurobiology to search for alterations in neuronal proteins reported to play pivotal roles in synaptic development. We found (i) early-occurring decreased expression of GAP43 in neurons, a gene required foraxon extension and structural organization of the presynaptic bouton, and (ii) early-occurring increased expression and activation of Notch1 in neurons. During CMS development, activation of Notch1 causes regression of both dendrites and axons, similar to events in prion diseases. These data suggest that PrPSc accumulation in neurons induces programmed dendritic atrophy (""""""""dendritic apoptosis"""""""") and programmed presynaptic bouton dysfunction and degeneration {""""""""synaptic apoptosis""""""""), which are analogous to PrPSc-induced programmed nerve cell death (apoptosis). The central specific aim is to test the hypothesis that PrPSc formation and accumulation in plasma membranes cause early-occurring synaptic abnormalities by activating Notch1. However, our previous studies argue that PrPSc is likely to affect synapses via alternative pathways. Therefore, we will an alternative hypothesis that posits that synaptic dysfunction and degeneration are caused by both Notch1-dependent and Notch1-independent pathways. The generation of synthetic prion strains, which have a unique PrPSc accumulation phenotype, provide us with a new tool to test whether or not the stereotypical progression of neurodegeneration found with natural RML prions is the same for all prion strains, including synthetic prion strains. Alternatively, each prion strain may trigger neurodegeneration by different molecular and cellular pathways, which may represent another defining prion strain characteristic.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010770-14
Application #
7309775
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
14
Fiscal Year
2006
Total Cost
$118,263
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
O'Brien, Connor J; Droege, Daniel G; Jiu, Alexander Y et al. (2018) Photoredox Cyanomethylation of Indoles: Catalyst Modification and Mechanism. J Org Chem 83:8926-8935
Condello, Carlo; Lemmin, Thomas; Stöhr, Jan et al. (2018) Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115:E782-E791
Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 135:49-63
Lim, Kwang Hun; Dasari, Anvesh K R; Hung, Ivan et al. (2016) Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR. Biochemistry 55:1941-4
Elkins, Matthew R; Wang, Tuo; Nick, Mimi et al. (2016) Structural Polymorphism of Alzheimer's ?-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. J Am Chem Soc 138:9840-52
Watts, Joel C; Giles, Kurt; Saltzberg, Daniel J et al. (2016) Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions. J Virol 90:9558-9569
Dunn, Joshua G; Weissman, Jonathan S (2016) Plastid: nucleotide-resolution analysis of next-generation sequencing and genomics data. BMC Genomics 17:958
Giles, Kurt; Berry, David B; Condello, Carlo et al. (2016) Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice. J Pharmacol Exp Ther 358:537-47
Patzke, Christopher; Acuna, Claudio; Giam, Louise R et al. (2016) Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation. J Exp Med 213:499-515
Ahlenius, Henrik; Chanda, Soham; Webb, Ashley E et al. (2016) FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice. Proc Natl Acad Sci U S A 113:8514-9

Showing the most recent 10 out of 179 publications