title: CDK5 is essential for soluble amyloid β-induced degradation of GKAP and remodeling of the synaptic actin cytoskeleton.
abstract: The early stages of Alzheimer's disease are marked by synaptic dysfunction and loss. This process results from the disassembly and degradation of synaptic components, in particular of scaffolding proteins that compose the post-synaptic density (PSD), namely PSD95, Homer and Shank. Here we investigated in rat frontal cortex dissociated culture the mechanisms involved in the downregulation of GKAP (SAPAP1), which links the PSD95 complex to the Shank complex and cytoskeletal structures within the PSD. We show that Aβ causes the rapid loss of GKAP from synapses through a pathway that critically requires cdk5 activity, and is set in motion by NMDAR activity and Ca(2+) influx. We show that GKAP is a direct substrate of cdk5 and that its phosphorylation results in polyubiquitination and proteasomal degradation of GKAP and remodeling (collapse) of the synaptic actin cytoskeleton; the latter effect is abolished in neurons expressing GKAP mutants that are resistant to phosphorylation by cdk5. Given that cdk5 also regulates degradation of PSD95, these results underscore the central position of cdk5 in mediating Aβ-induced PSD disassembly and synapse loss.
authors.affiliation: Neuroadaptation Group, Max Planck Institute of Psychiatry, Munich, Germany. Francesco.Roselli@fmi.ch
authors.forename: Francesco
authors.initials: F
authors.lastname: Roselli
authors.forename: Paolo
authors.initials: P
authors.lastname: Livrea
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology*; D000199:Actins / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000235:genetics; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D057907:Post-Synaptic Density / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology
chemical_list: D000199:Actins; D016229:Amyloid beta-Peptides; D015220:Calcium Channels; C491276:Dlgap1 protein, rat; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D051360:Cyclin-Dependent Kinase 5; D046988:Proteasome Endopeptidase Complex