The neurotrophins, NGF, BDNF, NT-3 and NT-4, represent a family of proteins essential for the development of the vertebrate nervous system. In addition to classical effects upon neuronal cell survival, neurotrophins also can regulate axonal and dendritic growth, synaptic structure and connections, neurotransmitter release, long-term potentiation and synaptic plasticity. Each neurotrophin can signal through two different cell surface receptors, Trk receptor tyrosine kinases and the p75 neurotrophin receptor, a member of the TNF receptor superfamily. Given the wide number of activities now associated with neurotrophins, it is likely additional regulatory events and signaling systems are involved. In this application, we will focus on a new and unexpected mechanism. Intramembraneous cleavage of the p75 receptor by gamma-secretase results in the release of the intracellular domain. This is the first known example of this activity in the TNF receptor superfamily. Significantly, the cleavage of p75 has been mapped to the same location as amyloid precursor protein (APR). Cleavage-resistant forms of p75 have been created to test the functional significance of gamma-secretase cleavage and the effect on p75 signaling activities. The functional consequences of p75 cleavage will be tested upon Trk receptor signaling, as well as axonal regeneration events. The p75 receptor is known to interact with cytoplasmic proteins that can translocate to the nucleus. Among many proteins that interact with p75, we will follow SC-1, a novel zinc finger protein that translocates to the nucleus. Since p75 is frequently upregulated after injury, these studies will provide further insight into mechanisms responsible for neurotrophins during inflammation and neurodegenerative disease states, such as Alzheimer's dementia and amyotrophic lateral sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025970-05
Application #
7848871
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wise, Bradley C
Project Start
2006-09-30
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$327,343
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Zhang, Guoan; Bowling, Heather; Hom, Nancy et al. (2014) In-depth quantitative proteomic analysis of de novo protein synthesis induced by brain-derived neurotrophic factor. J Proteome Res 13:5707-14

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