The recent identification of transcription factors (TFs) that can induce conversion of fibroblasts into pluripotent stem (IPS) cells makes it potentially possible to generate patient-specific neurons from fibroblasts. However, the neurons thus produced are difficult to obtain. The present project builds on preliminary results demonstrafing that it is possible to direcfiy convert adult fibroblasts or other adult non- neuronal cells into neurons, referred to as 'induced neuronal cells'(iN cells), without an iPS intermediate. The resulfing IN cells have all ofthe functional properties of neurons, including the ability to form funcfional synapses as assayed electrophysiology. Thus, the IN cell technology provides a novel, more facile approach to generating and studying human neurons, and opens up a new avenue to invesfigafing neurons from patients with various neurodegenerafive diseases. However, at this point the IN cell technology has only been employed to fibroblasts from young mice, and the effect of aging on iN cell generation and/or the generation of IN cells from human fibroblasts have not yet been established. Therefore, the present application proposes experiments in three specific aims that will systematically investigate the effect of aging on iN cell generafion (specific aim 1), develop the technology to generate IN cells from human fibroblasts (specific aim 2), and use the IN cell technology to study the properties of mouse and human neurons containing mutafions that are known to cause Alzheimer's disease (specific aim 3).
These aims will be pursued by a combinafion of fissue culture experiments with cells cultured from mice and humans, cell biology, molecular biology, and electrophysiology. Together, the experiments proposed in this applicafion will develop a new avenue for studying human neurons and for invesfigafing the relationship of aging and neurodegenerafion, with the long term goal of using this technology for a better understanding of human aging and human disease.

Public Health Relevance

This application will develop methods to generate neurons direcfiy from non-neuronal cells, allowing the production of neurons from skin fibroblasts of human patients. These methods will then be used to test the effects of aging and of Alzheimer's disease mutations on neuronal biology, with the long-term goal of establishing a better understanding of how aging and Alzheimer's disease alter neuronal function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010770-20
Application #
8448176
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
20
Fiscal Year
2013
Total Cost
$309,886
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Watts, Joel C; Prusiner, Stanley B (2014) Mouse models for studying the formation and propagation of prions. J Biol Chem 289:19841-9
Watts, Joel C; Condello, Carlo; Stöhr, Jan et al. (2014) Serial propagation of distinct strains of A? prions from Alzheimer's disease patients. Proc Natl Acad Sci U S A 111:10323-8
Burré, Jacqueline; Sharma, Manu; Südhof, Thomas C (2014) ?-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci U S A 111:E4274-83
Chanda, Soham; Ang, Cheen Euong; Davila, Jonathan et al. (2014) Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Reports 3:282-96
Ang, Cheen Euong; Wernig, Marius (2014) Induced neuronal reprogramming. J Comp Neurol 522:2877-86
Silber, B Michael; Gever, Joel R; Rao, Satish et al. (2014) Novel compounds lowering the cellular isoform of the human prion protein in cultured human cells. Bioorg Med Chem 22:1960-72
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
Li, Zhe; Gever, Joel; Rao, Satish et al. (2013) Discovery and Preliminary SAR of Arylpiperazines as Novel, Brainpenetrant Antiprion Compounds. ACS Med Chem Lett 4:397-401
Berry, David B; Lu, Duo; Geva, Michal et al. (2013) Drug resistance confounding prion therapeutics. Proc Natl Acad Sci U S A 110:E4160-9

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