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

75 Pages Posted: 10 Jan 2019 Publication Status: Published

See all articles by Shamsideen A. Ojelade

Shamsideen A. Ojelade

Baylor University, College of Medicine, Department of Neurology; Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

Tom V. Lee

Baylor University, College of Medicine, Department of Neurology; Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

Nikolaos Giagtzoglou

Baylor University, College of Medicine, Department of Neurology

Lei Yu

Rush University Medical Center - Rush Alzheimer’s Disease Center

Berrak Ugur

Baylor University - Program in Developmental Biology

Lita Duraine

Baylor College of Medicine - Howard Hughes Medical Institute

Zhongyuan Zuo

Baylor College of Medicine - Department of Molecular and Human Genetics

Vladislav Petyuk

Pacific Northwest National Laboratory

Philip L. De Jager

Columbia University - Center for Translational and Systems Neuroimmunology

David A. Bennett

Rush University Medical Center - Rush Alzheimer’s Disease Center

Benjamin R. Arenkiel

Baylor University, College of Medicine, Howard Hughes Medical Institute; Baylor University - Jan and Dan Duncan Neurologic Research Institute; Baylor University, College of Medicine, Program in Developmental Biology; Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

Hugo J. Bellen

Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

Joshua M. Shulman

Baylor University, College of Medicine, Department of Neurology; Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

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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

Suggested Citation

Ojelade, Shamsideen A. and Lee, Tom V. and Giagtzoglou, Nikolaos and Yu, Lei and Ugur, Berrak and Duraine, Lita and Zuo, Zhongyuan and Petyuk, Vladislav and De Jager, Philip L. and Bennett, David A. and Arenkiel, Benjamin R. and Bellen, Hugo J. and Shulman, Joshua M., Cindr, the Drosophila Homolog of the CD2AP Alzheimer's Disease Susceptibility Gene, is Required for Synaptic Transmission and Proteostasis (January 8, 2019). Available at SSRN: https://ssrn.com/abstract=3312120 or http://dx.doi.org/10.2139/ssrn.3312120
This version of the paper has not been formally peer reviewed.

Shamsideen A. Ojelade

Baylor University, College of Medicine, Department of Neurology

Houston, TX
United States

Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

6621 Fannin St
Houston, TX 77030
United States

Tom V. Lee

Baylor University, College of Medicine, Department of Neurology

Houston, TX
United States

Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

6621 Fannin St
Houston, TX 77030
United States

Nikolaos Giagtzoglou

Baylor University, College of Medicine, Department of Neurology

Houston, TX
United States

Lei Yu

Rush University Medical Center - Rush Alzheimer’s Disease Center ( email )

1700 West Van Buren Street, TOB Suite 126B
Chicago, IL 60611
United States

Berrak Ugur

Baylor University - Program in Developmental Biology

Houston, TX 77030
United States

Lita Duraine

Baylor College of Medicine - Howard Hughes Medical Institute

Houston, TX 77030
United States

Zhongyuan Zuo

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Vladislav Petyuk

Pacific Northwest National Laboratory

901 D Street
370 L'Enfant Promenade, S.W.
Washington, DC 20024-2115
United States

Philip L. De Jager

Columbia University - Center for Translational and Systems Neuroimmunology

630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

David A. Bennett

Rush University Medical Center - Rush Alzheimer’s Disease Center

1700 West Van Buren Street, TOB Suite 126B
Chicago, IL 60611
United States

Benjamin R. Arenkiel

Baylor University, College of Medicine, Howard Hughes Medical Institute

Houston, TX 77030
United States

Baylor University - Jan and Dan Duncan Neurologic Research Institute

Houston, TX
United States

Baylor University, College of Medicine, Program in Developmental Biology

Houston, TX 77030
United States

Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

Houston, TX
United States

Hugo J. Bellen

Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

6621 Fannin St
Houston, TX 77030
United States

Joshua M. Shulman (Contact Author)

Baylor University, College of Medicine, Department of Neurology ( email )

Houston, TX
United States

Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute ( email )

6621 Fannin St
Houston, TX 77030
United States

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