cindr, the Drosophila Homolog of the CD2AP Alzheimer’s Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis
Shamsideen A. Ojelade,
Tom V. Lee,
Nikolaos Giagtzoglou,
Lei Yu,
Berrak Ugur,
Yarong Li,
Lita Duraine,
Zhongyuan Zuo,
Vlad Petyuk,
Philip L. De Jager,
David A. Bennett,
Benjamin R. Arenkiel,
Hugo J. Bellen,
Joshua M. Shulman
Affiliations
Shamsideen A. Ojelade
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
Tom V. Lee
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
Nikolaos Giagtzoglou
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
Lei Yu
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
Berrak Ugur
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
Yarong Li
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
Lita Duraine
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Zhongyuan Zuo
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Vlad Petyuk
Pacific Northwest National Laboratory, Richland, WA 99354, USA
Philip L. De Jager
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
David A. Bennett
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
Benjamin R. Arenkiel
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
Hugo J. Bellen
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
Joshua M. Shulman
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; Corresponding author
Summary: 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. : CD2AP is an Alzheimer’s disease susceptibility gene with uncertain brain function. Ojelade et al. discover that mutation of the Drosophila homolog cindr disrupts ubiquitin-proteasome system activity, causing calcium dyshomeostasis and impaired synaptic vesicle recycling and release. Cd2ap null mice and human brain proteomic studies support a conserved role in synaptic proteostasis. Keywords: PMCA, synapsin, ubiquitin-proteasome system, 14-3-3, GWAS, neurofibrillary tangles, Tau, endocytosis, exocytosis, neuromascular junction
