cindr, the Drosophila Homolog of the CD2AP Alzheimer’s Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis

摘要

The Alzheimer’s disease (AD) susceptibility gene,CD2-associated protein (CD2AP), encodes an actinbinding adaptor protein, but its function in the nervoussystem is largely unknown. Loss of theDrosophila ortholog cindr enhances neurotoxicityof human Tau, which forms neurofibrillary tangle pathologyin AD. We show that Cindr is expressed inneurons and present at synaptic terminals. cindr mutantsshow impairments in synapse maturation andboth synaptic vesicle recycling and release. Cindr associatesand genetically interacts with 14-3-3z, regulatesthe ubiquitin-proteasome system, and affectsturnover of Synapsin and the plasma membrane calciumATPase (PMCA). Loss of cindr elevates PMCAlevels and reduces cytosolic calcium. Studies ofCd2ap null mice support a conserved role in synapticproteostasis, and CD2AP protein levels are inverselyrelated to Synapsin abundance in human postmortembrains. Our results reveal CD2AP neuronal requirementswith relevance to AD susceptibility,including for proteostasis, calcium handling, andsynaptic structure and function.