Aberrant folding of proteins is a feature common to many neurodegenerative diseases, including prion disease, Huntington's disease, Alzheimer's disease, and others. Misfolded proteins may adopt several distinct tertiary and quaternary conformations as they progress from a normal monomeric state and ultimately end up in large aggregated protein deposits in the brain. The role of intermediate protein conformations in the disease process remains elusive, especially in prion and Huntington's diseases. In my current research, I have found that prion protein intermediates that are sensitive to protease digestion appear to contribute significantly to disease pathology. Historically, attention in this field has focused primarily on the protease-resistant forms of the prion protein in the disease process. I have also developed a new technique for detecting protease-sensitive pathological intermediates (Colby et. al., PNAS, 2007). During the mentored phase of this application, I propose to apply this technique to study these intermediates'structure and their role in neurodegeneration. I will continue some aspects of this work as I transition to an independent position, and will also begin applying what I have learned to Huntington's disease. My mentor, Dr. Prusiner, has given me leeway to begin some preliminary studies for my independent work during the mentored phase, in order to facilitate my transition to independence. My more long term career research goals are to understand the unifying factors that relate protein misfolding to neurodegeneration in so many diseases, each associated with misfolding of a different protein. Before I begin working in an independent academic position, I need additional time to strengthen my training in the use of mouse models and in structural biology, especially given my background in Chemical engineering. Stanley Prusiner's Institute for Neurodegenerative Diseases at UCSF is an ideal environment for me to obtain this training. Aside from Dr. Prusiner's recognized leadership in this field, there are many critical collaborators affiliated with the IND who will contribute to my training. Public Health Relevance: The proposed research seeks to understand the causes of neurodegerative diseases, including Huntington's disease and Cruetzfeldt-Jakob disease. An additional objective of the work is to develop tests for the diagnosis of Crutezfeldt-Jakob disease. The research may also impact Alzheimer's disease and Parkinson's disease research, because these diseases have common causes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Career Transition Award (K99)
Project #
5K99NS064173-02
Application #
7755874
Study Section
Special Emphasis Panel (ZNS1-SRB-M (61))
Program Officer
Wong, May
Project Start
2009-01-01
Project End
2010-06-30
Budget Start
2010-01-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$90,000
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Morozova, Olga A; Gupta, Sharad; Colby, David W (2015) Prefibrillar huntingtin oligomers isolated from HD brain potently seed amyloid formation. FEBS Lett 589:1897-903
Barbaro, Brett A; Lukacsovich, Tamas; Agrawal, Namita et al. (2015) Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease. Hum Mol Genet 24:913-25
Doolan, Kyle M; Colby, David W (2015) Conformation-dependent epitopes recognized by prion protein antibodies probed using mutational scanning and deep sequencing. J Mol Biol 427:328-40
Watts, Joel C; Giles, Kurt; Patel, Smita et al. (2014) Evidence that bank vole PrP is a universal acceptor for prions. PLoS Pathog 10:e1003990
Morozova, Olga A; March, Zachary M; Robinson, Anne S et al. (2013) Conformational features of tau fibrils from Alzheimer's disease brain are faithfully propagated by unmodified recombinant protein. Biochemistry 52:6960-7
Colby, David W; Wain, Rachel; Baskakov, Ilia V et al. (2010) Protease-sensitive synthetic prions. PLoS Pathog 6:e1000736
Colby, David W; Giles, Kurt; Legname, Giuseppe et al. (2009) Design and construction of diverse mammalian prion strains. Proc Natl Acad Sci U S A 106:20417-22