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CNTNAP2 Protein Is Degraded by the Ubiquitin–Proteasome System and the Macroautophagy-Lysosome Pathway

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Abstract

Contactin-associated protein-like 2 (CNTNAP2) gene, located on chromosome 7q35, is one of the largest genes in the human genome. CNTNAP2 protein is a type-I transmembrane protein specifically expressed in the nervous system, with versatile roles in the axonal organization, synaptic functions, neuronal migration, and functional connectivity. CNTNAP2 has been widely investigated as a risk gene for autism spectrum disorder (ASD), and recent studies also implicated CNTNAP2 in Alzheimer’s disease (AD). Knowledge of the regulations on CNTNAP2’s life cycle is necessary for understanding the related physiological functions and pathological conditions. However, the mechanisms underlying CNTNAP2 protein degradation remain elusive. Therefore, we systematically investigated the half-life and degradation pathway of the human CNTNAP2 protein. We discovered that CNTNAP2 has C-terminal fragments (CTF), which may have essential physiological functions. Our results demonstrated that CNTNAP2 full-length protein and CTF have a short half-life of about 3–4 h. CNTNAP2 proteins are degraded by the ubiquitin–proteasome system and the macroautophagy-lysosome pathway, while the lysosome pathway is more common for CNTNAP2 degradation. This study will provide novel insights and valuable tools for CNTNAP2 functional research in physiological and pathological scenarios.

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Funding

This study was partly supported by Jack Brown and Family Alzheimer's Research Foundation. QZ and IBL are supported by the Four Year Fellowship for PhD and the Faculty of Medicine Graduate Award from the University of British Columbia. QZ received DMCBH Innovation Fund Graduate Trainee Award. IBL is also supported by Jock and Irene Graham Brain Endowment Award.

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Authors and Affiliations

  1. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Qing Zhang, Keenan Sterling, Fang Cai, Sheng Yu, Isabel Bestard-Lorigados & Weihong Song

  2. Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, School of Mental Health and Kangning Hospital, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Lu Xu, Mengen Xing & Weihong Song

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  1. Qing Zhang
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  3. Lu Xu
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Contributions

QZ and WS conceived and designed the experiments. QZ, KS, FC, LX, and SY performed the experiments. QZ, KS, FC, LX, XM, IBL, and WS analyzed and contributed reagents/materials/analytical tools. QZ and WS wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Weihong Song.

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Animal experiments were approved by the University of British Columbia Animal Care and Use Committee (Protocol ID: A21-0303, Neuronal Culture) and conducted in accordance with guidelines.

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Zhang, Q., Sterling, K., Xu, L. et al. CNTNAP2 Protein Is Degraded by the Ubiquitin–Proteasome System and the Macroautophagy-Lysosome Pathway. Mol Neurobiol 60, 2455–2469 (2023). https://doi.org/10.1007/s12035-023-03227-9

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