The function and viability of neurons is frequently dependent upon secreted growth factors. Although most extensively investigated in the developing nervous system neurotrophic factors are important in the adult brain and have been examined as therapeutic modalities in adult neurodegenerative conditions. Therefore, the isolation of proteins in adult brain with neurotrophic activity could have broad implications both for our understanding of the maintenance of neuronal integrity and function in the mature nervous system and as potential therapeutic agents for a range of neurological and psychiatric disorders. We identified a family of brain-specific proteins (Cbln1-Cbln4), termed synaptotrophins that have properties of adult neurotrophic factors. Cbln1 and Cbln3 are secreted glycoproteins that are co-expressed in mature cerebellar granule cells and form trimeric complexes that are structurally related to tumor necrosis factor-alpha (TNFalpha). Elimination of Cbln1 through homologous recombination in mice causes ataxia, marked structural and physiological defects in granule celI-Purkinje cell synaptic interactions and the progressive degeneration of adult cerebellar granule neurons. Thus Cbln1 is the prototype of a novel class of factor that regulates synaptic stability and function and neuronal survival. Remarkably, loss of the orphan glutamate delta2 receptor (GluRdelta2) in Purkinje cells mimics the phenotype of the cbln1-null mouse. Thus, presynaptic Cbln1 and postsynaptic GluRdelta2 may be components of a novel trophic signaling pathway. This mechanism likely exists elsewhere in brain having implications for neuropsychiatric (disrupted synaptic transmission) and neurodegenerative disorders (neuronal loss and functional impairment) in man. In this application we take advantage of the structural and functional properties of TNFalpha and GluRdelta2 to elucidate the molecular bases of the neural deficits in cbln1-null mice and characterize the components of the Cbln1 signaling pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042828-05
Application #
7539161
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Mamounas, Laura
Project Start
2004-12-10
Project End
2010-11-30
Budget Start
2008-12-01
Budget End
2010-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$328,901
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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