Our revisions of Project 4 are adapted to the results of our first drug trials with the g-secretase inhibitor (GSI), LY-411,575, and the Reviewer1 critiques. The focus of our first version of Project 4 was to expand on our discovery that activation of the Notch-1 represser signaling pathway links rPrPSc accumulation in synaptic regions with early occurring dendritic atrophy. The Reviewers doubted we could do the experiments in mature prion-infected brain spheres as we proposed and objected to our focus on the pathogenic role of rPrPSc ignoring other potentially pathogenic PrP molecules including tmPrP that adopts a transmembrane topology, GPI-anchorless PrP(GPI0/0), and PrP(P101L) that cause neurodegeneration without rPrPSc. Since the submission of the first proposal we found that oral GSI plus quinacrine (Q) therapy decreased rPrPSc levels in brain by 90%, prevented ~50% of the expected dendritic atrophy and loss, but had equivocal effects on reactive microgliomatosis and reactive astrocytic gliosis. Although the benefits of that combination of drugs were the best ever achieved with an animal model of scrapie, the incompleteness of the effects of treatment argued that many other neurodegenerative factors were not accounted for. For these reasons the overall aim of the revised proposal is to organize the multiple factors causing neurodegeneration and preventing recovery during prion diseases into a hierarchical or ranked order of importance. To accomplish this, 5 Specific Aims are proposed to address both global changes in the brain while still addressing specific critical issues.
Aim #1 addresses our data-based hypothesis that rPrPSc is the primary cause of neurodegeneration by testing the hypothesis that it begins the process of Notch-1 activation, which leads to dendritic atrophy.
Aim #2 uses multiple transgenic (Tg) mice constructed in Stanley Prusiner's Lab that exclusively express anchorless PrP, Tg(PrP GPI0/0);95% transmembrane PrP, Tg(SHaPrP KH-?II);100% GPI-anchored PrPc, Tg(SHaPrP DSTE);and Tg(GSS P101L) to test the relative contribution of each pathogenic PrP form to early occurring synaptic degeneration and late occurring neuronal loss in scrapie- type prion disease.
Aim #3 tests the hypothesis that inhibitory interneurons are more vulnerable than excitatory neurons during scrapie.
Aim #4 uses the unique expertise of Leroy Hood's Institute to construct gene regulatory networks that will compare variations in neocortical and thalamic transcriptomes in uninfected control mice, RML prion infected mice, and RML infected mice treated with dual GSI + Q therapy. Our goal is to learn which functional gene pathways are changed with infection and which of those are corrected or not corrected by treatment.
Aim #5 is to continue to develop and use a mature infectable brains sphere to test our hypotheses.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mc Laughlin Research Institute
Great Falls
United States
Zip Code
Chaverra, Marta; George, Lynn; Mergy, Marc et al. (2017) The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system. Dis Model Mech 10:605-618
Daude, Nathalie; Lee, Inyoul; Kim, Taek-Kyun et al. (2016) A Common Phenotype Polymorphism in Mammalian Brains Defined by Concomitant Production of Prolactin and Growth Hormone. PLoS One 11:e0149410
Wegmann, Susanne; Maury, Eduardo A; Kirk, Molly J et al. (2015) Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity. EMBO J 34:3028-41
Anderson, Sarah R; Lee, Inyoul; Ebeling, Christine et al. (2015) Disrupted SOX10 function causes spongiform neurodegeneration in gray tremor mice. Mamm Genome 26:80-93
Park, Laibaik; Koizumi, Kenzo; El Jamal, Sleiman et al. (2014) Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. Stroke 45:1815-21
Lausted, Christopher; Lee, Inyoul; Zhou, Yong et al. (2014) Systems approach to neurodegenerative disease biomarker discovery. Annu Rev Pharmacol Toxicol 54:457-81
Stöhr, Jan; Condello, Carlo; Watts, Joel C et al. (2014) Distinct synthetic A? prion strains producing different amyloid deposits in bigenic mice. Proc Natl Acad Sci U S A 111:10329-34
Gunn, Teresa M; Carlson, George A (2013) RML prions act through Mahogunin and Attractin-independent pathways. Prion 7:267-71
Flores, Mauricio; Glusman, Gustavo; Brogaard, Kristin et al. (2013) P4 medicine: how systems medicine will transform the healthcare sector and society. Per Med 10:565-576
George, Lynn; Chaverra, Marta; Wolfe, Lindsey et al. (2013) Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3+ progenitors and peripheral neurons. Proc Natl Acad Sci U S A 110:18698-703

Showing the most recent 10 out of 29 publications