Cindr, the Drosophila Homolog of the CD2AP Alzheimer's Disease Susceptibility Gene, is Required for Synaptic Transmission and Proteostasis

Abstract

The Alzheimer’s disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin-binding, adaptor protein, but its function in the nervous system is largely unknown. Loss of the Drosophila ortholog, cindr, enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. Here, we show that Cindr is expressed in Drosophila neurons and present at presynaptic terminals. Flies lacking cindr show impairments in synaptic maturation, as well as synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin protein and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and triggers reduction of cytosolic calcium. Studies of CD2AP mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are also inversely related to Synapsin abundance in human postmortem brains. Our results reveal novel CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure/function.

Keywords: calcium; PMCA; Synapsin; ubiquitin-proteasome system; Alzheimer’s Disease; 14-3-3; GWAS; neurofibrillary tangles; Tau; endocytosis; exocytosis; neuromuscular junction