Protein degradation by the ubiquitin-proteasome pathway plays an important role in the brain, yet the components regulating protein destruction in brain are poorly understood. In three complementary aims, we will determine whether F box proteins encoded by the Fbx2 gene family function as ubiquitin ligases to mediate glycoprotein quality control in neurons. In cell models, an array of molecular and biochemical approaches will be used to test whether Fbx2 regulates ubiquitin-dependent degradation of misfolded or unassembled glycoproteins, including the neurological disease proteins TorsinA and neuroserpin. The function of Fbx2 will then be further explored in vivo using a recently generated FBx2 knockout mouse model. Finally, the expression pattern and functional properties of other F box proteins encoded by the Fbx2 family will be defined. The proposed experiments are significant because they will provide insight into how neurons handle normal and abnormal glycoproteins and will increase fundamental knowledge about an important new class of ubiquitin ligases. The results may also have implications for the pathogenesis of two poorly understood neurological diseases, DYT1 dystonia and familial neuroserpin dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047535-04
Application #
7166048
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Murphy, Diane
Project Start
2004-01-01
Project End
2007-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$321,711
Indirect Cost
Name
University of Iowa
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Glenn, Kevin A; Nelson, Rick F; Wen, Hsiang M et al. (2008) Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases. J Biol Chem 283:12717-29
Nelson, Rick F; Glenn, Kevin A; Zhang, Yuzhou et al. (2007) Selective cochlear degeneration in mice lacking the F-box protein, Fbx2, a glycoprotein-specific ubiquitin ligase subunit. J Neurosci 27:5163-71
Nelson, Rick F; Glenn, Kevin A; Miller, Victor M et al. (2006) A novel route for F-box protein-mediated ubiquitination links CHIP to glycoprotein quality control. J Biol Chem 281:20242-51
Miller, Victor M; Nelson, Rick F; Gouvion, Cynthia M et al. (2005) CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. J Neurosci 25:9152-61