Analysis of Fbx2 Family of Ubiquitin Ligases

University Of Iowa, Iowa City IA

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Abstract

DESCRIPTION (provided by applicant): 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.