The Role of F-box Only Protein 2 (Fbxo2) in Amyloid Precursor Protein Processing and Synaptic Dynamics.

[摘要] Proper protein quality control is essential for neuronal health and function, and there is substantial evidence for the dysregulation of proteostasis in a wide range of neuropathological conditions including the most common neurodegenerative diseases. Diminished function of the Ubiquitin Proteasome System, the major cellular pathway for the clearance of toxic or unwanted proteins, likely contributes to disease pathogenesis through numerous - and as yet, incompletely understood - mechanisms.Here, I review recent studies exploring the role of the Ubiquitin Proteasome System in the most common neurodegenerative diseases.I then describe in-depth two research projects directed at further investigating one agent of the Ubiquitin Proteasome System whose expression is reduced in Alzheimer’s disease, the F-box Only Protein 2 (Fbxo2).Using cell-based models and an Fbxo2 knockout mouse, I present evidence for a role for Fbxo2 in the turnover and processing of the Amyloid Precursor Protein, believed to be the major causative protein in Alzheimer’s disease. I then show that the loss of Fbxo2 results in greater expression and surface localization of NMDA receptor subunits, and enhances the formation of axo-dendritic shaft synapses.Taken together, these studies support a central role for the Ubiquitin Proteasome System, and in particular Fbxo2, in the turnover and handling of key proteins in the pathogenesis of Alzheimer’s disease and the regulation of synaptic connections.

[发布机构] University of Michigan

[效力级别] Synapse

[关键词] Neuroscience;Synapse;Molecular;Cellular and Developmental Biology;Science;Neuroscience