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

• DOI: 10.1038/s41420-025-02414-y
• Publication Date: 2025-04-06T01:55:37Z
• Authors: Fanghui Chen; Minghui Xiang; Zhipeng Wang; Fan Yang; Junzhi Zhou; Zihan Deng; Susu Wang; Ping Li; Jieqi Tew; Wei Zhang; Honglin Li; Yong Teng; Xiaobin Zhu; Yafei Cai
• Keywords: Knockout mouse; Conditional gene knockout

Abstract CDK5RAP3 is a binding protein of CDK5 activating proteins and also one the key co-factors E3 enzyme in UFMylation system. Several reports have implicated involvement other components system neuronal development multiple psychiatric disorders. However, precise role neurons remains elusive. In this study, we generated neuron-specific knockout mice (CDK5RAP F/F : Nestin-Cre). conditional (CDK5RAP3 CKO) exhibited severe encephalo-dysplasia slower developmental trajectory compared to wild-type (WT) succumbed postnatal demise by day 14. Transcriptome sequencing unveiled that deficiency affects synapse formation, transmembrane trafficking physiological programs brain. Morphological analysis demonstrated leads increased SLC17A6 N-glycosylase (RPN1 ALG2) expression, while causing endoplasmic reticulum (ER) stress. vitro experiments utilizing ROSA26-ERT2Cre MEFs were conducted elucidate similar mechanism following deletion. Both vivo vitro, significantly expression N-glycosylases ALG2), as well total amount glycoproteins. may potentially maintain balance enhancing degradation RPN1 ALG2 through proteolytic pathways autophagy. This study underscores indispensable sheds new light on drug discovery endeavors targeting early brain abnormalities.