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Cell Rep. 2019 Aug 13;28(7):1799-1813.e5. doi: 10.1016/j.celrep.2019.07.041.

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

Author information

1
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
2
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
3
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
5
Pacific Northwest National Laboratory, Richland, WA 99354, USA.
6
Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute, Columbia University Medical Center, New York, NY 10032, USA; Cell Circuits Program, Broad Institute, Cambridge, MA 02142, USA.
7
Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
8
Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
9
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: joshua.shulman@bcm.edu.

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. We show that Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and both synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and reduces cytosolic calcium. Studies of Cd2ap null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function.

KEYWORDS:

14-3-3; GWAS; PMCA; Tau; endocytosis; exocytosis; neurofibrillary tangles; neuromascular junction; synapsin; ubiquitin-proteasome system

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