2. Academic Validation
  3. Neuronal CDK5RAP3 deficiency leads to encephalo-dysplasia via upregulation of N-glycosylases and glycogen deposition

Neuronal CDK5RAP3 deficiency leads to encephalo-dysplasia via upregulation of N-glycosylases and glycogen deposition

  • Cell Death Discov. 2025 Apr 6;11(1):146. doi: 10.1038/s41420-025-02414-y.
Fanghui Chen 1,  Minghui Xiang 1,  Zhipeng Wang 1,  Fan Yang 2,  Junzhi Zhou 3,  Zihan Deng 1,  Susu Wang 1,  Ping Li 1,  Jieqi Tew 1,  Wei Zhang 1,  Honglin Li 4,  Yong Teng 5,  Xiaobin Zhu 6,  Yafei Cai 7
Affiliations

Affiliations

  • 1 College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
  • 2 Department of Human Anatomy, Bengbu Medical College, Bengbu, 233030, China.
  • 3 School of Basic Medicine, Guangdong Medical University, Dongguan, 523808, China.
  • 4 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
  • 5 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA.
  • 6 Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan City, 430071, China. xiaobinzhu@whu.edu.cn.
  • 7 College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China. ycai@njau.edu.cn.
PMID: 40188151 DOI: 10.1038/s41420-025-02414-y
Abstract

CDK5RAP3 is a binding protein of CDK5 activating proteins and also one of the key co-factors of the E3 enzyme in the UFMylation system. Several reports have implicated the involvement of CDK5 and Other components of the UFMylation system in neuronal development and multiple psychiatric disorders. However, the precise role of CDK5RAP3 in neurons remains elusive. In this study, we generated CDK5RAP3 neuron-specific knockout mice (CDK5RAPF/F: Nestin-Cre). CDK5RAP3 conditional knockout (CDK5RAP3 CKO) mice exhibited severe encephalo-dysplasia and a slower developmental trajectory compared to wild-type (WT) mice and succumbed to postnatal demise by day 14. Transcriptome Sequencing unveiled that CDK5RAP3 deficiency affects synapse formation, transmembrane trafficking and physiological programs in the brain. Morphological analysis demonstrated that neuronal CDK5RAP3 deficiency leads to increased SLC17A6 and N-glycosylase (RPN1 and ALG2) protein expression, and while causing endoplasmic reticulum (ER) stress. In vitro experiments utilizing CDK5RAP3F/F: ROSA26-ERT2Cre MEFs were conducted to elucidate similar mechanism following CDK5RAP3 deletion. Both in vivo and in vitro, CDK5RAP3 deficiency significantly increased the expression of N-glycosylases (RPN1 and ALG2), as well as the total amount of glycoproteins. CDK5RAP3 may potentially maintain a balance by enhancing the degradation of RPN1 and ALG2 through proteolytic degradation pathways and Autophagy. This study underscores the indispensable role of CDK5RAP3 in neuronal development and sheds new light on drug discovery endeavors targeting early brain abnormalities.

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