Palmitoylation of cdc42 Promotes Spine Stabilization and Rescues Spine Density Deficit in a Mouse Model of 22q11.2 Deletion Syndrome
| Autor: | Alexander Wirth, Dominique Muller, M. De Roo, Evgeni Ponimaskin, Irina Nikonenko, Enora Moutin, Thomas Stefanelli |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Anatomic 0301 basic medicine Genetically modified mouse Dendritic spine Dendritic Spines Lipoylation Cognitive Neuroscience Green Fluorescent Proteins Hippocampus Nerve Tissue Proteins In Vitro Techniques Biology Hippocampal formation Mice 03 medical and health sciences Cellular and Molecular Neuroscience Organ Culture Techniques Palmitoylation Transduction Genetic DiGeorge syndrome DiGeorge Syndrome medicine Animals Humans RNA Small Interfering cdc42 GTP-Binding Protein SPINE (molecular biology) Microscopy Confocal ddc:617 Age Factors Membrane Proteins Phosphoproteins medicine.disease Phosphoric Monoester Hydrolases ddc:616.8 Disease Models Animal Microscopy Electron 030104 developmental biology Animals Newborn Cdc42 GTP-Binding Protein Mutation Neuroscience Acyltransferases |
| Zdroj: | Europe PubMed Central Cerebral Cortex (2016) |
| ISSN: | 1460-2199 1047-3211 |
| DOI: | 10.1093/cercor/bhw183 |
| Popis: | Palmitoylation of cdc42 Promotes Spine Stabilization and Rescues Spine Density Deficit in a Mouse Model of 22q11.2 Deletion Syndrome. 22q11.2 deletion syndrome (22q11DS) is associated with learning and cognitive dysfunctions and a high risk of developing schizophrenia. It has become increasingly clear that dendritic spine plasticity is tightly linked to cognition. Thus, understanding how genes involved in cognitive disorders affect synaptic networks is a major challenge of modern biology. Several studies have pointed to a spine density deficit in 22q11DS transgenic mice models. Using the LgDel mouse model, we first quantified spine deficit at different stages using electron microscopy. Next we performed repetitive confocal imaging over several days on hippocampal organotypic cultures of LgDel mice. We show no imbalanced ratio between daily spine formation and spine elimination, but a decreased spine life expectancy. We corrected this impaired spine stabilization process by overexpressing ZDHHC8 palmitoyltransferase, whose gene belongs to the LgDel microdeletion. Overexpression of one of its substrates, the cdc42 brain-specific variant, under a constitutively active form (cdc42-palm-CA) led to the same result. Finally, we could rescue spine density in vivo, in adult LgDel mice, by injecting pups with a vector expressing cdc42-palm-CA. This study reveals a new role of ZDHHC8-cdc42-palm molecular pathway in postsynaptic structural plasticity and provides new evidence in favor of the dysconnectivity hypothesis for schizophrenia. |
| Databáze: | OpenAIRE |
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