In collaboration with other researchers, Prof. Da Jia's team from the West China Second University Hospital(WCSUH) and State Key Laboratory of Biotherapy recently published two high-level papers in Nature Structural Molecular Biology (corresponding authors Da Jia and Ning Gao from the School of Life Sciences, Beijing University) and Molecular Biomedicine (corresponding authors Da Jia, WCSUH’s Yingfeng Tu and Xiao-tang Cai). The papers elucidated the molecular mechanism of GMPPA and GMPPB in maintaining the level of GDP mannose in vivo, revealed the causes of congenital glycosylation diseases due to GMPPA and GMPPB mutations, and discussed their possible treatments. This study provides an important reference for the clinical diagnosis and treatment of congenital glycosylation related diseases.
The study, published in Molecular Biomedicine, reported a 1-year-old male who came to WCSUH for treatment. The patient developed muscle weakness of upper and lower limbs as early as 1 month old, and muscle biopsy showed chronic myopathy. “His brain showed smaller size of cerebellar hemisphere and enlarged bilateral lateral ventricles, detected by MRI at his fetal stage (34 week), which indicated a possibility of cerebellar hypoplasia”(Results)
“By measuring enzymatic activities of 17 reported GMPPB mutants identified in patients diagnosed with GMPPB-CDG, we discover that all tested GMPPB variants exhibit significantly decreased enzymatic activity. Using a zebrafish model, we find that GMPPB is required for neuronal and muscle development, and further demonstrate that enzymatic activity of GMPPB mutants correlates with muscular and neuronal phenotypes in zebrafish. Taken together, our findings discover the importance of GMPPB enzymatic activity for the pathogenesis of GMPPB-CDG, and shed light for the development of additional indicators and therapeutic strategy.”(Abstract)
Fig. 1: Clinical sample data and gene mutation analysis of patients
“We also examined the effects of the missense mutations on the subcellular localization of GMPPB. We found that V111G mutation caused increased nuclear localization of GMPPB, while G214S mutant seemed to lose nuclear localization”(Results)
In the study published in Nature Structural Molecular Biology, the authors analyzed the freeze electron microscopic structure of GMPPA and GMPPB complexes, and revealed how GMPPA and GMPPB cooperate to maintain the homeostasis of GDP mannose in vivo by using biochemical, cellular and zebrafish models. “Here, we report the cryo-EM structures of human GMPPA–GMPPB complex, the protein machinery responsible for GDP-Man synthesis, in complex with GDP-Man or GTP. Unexpectedly, we find that the catalytically inactive subunit GMPPA displays a much higher affinity to GDP-Man than the active subunit GMPPB and, subsequently, inhibits the catalytic activity of GMPPB through a unique C-terminal loop of GMPPA. Importantly, disruption of the interactions between GMPPA and GMPPB or the binding of GDP-Man to GMPPA in zebrafish leads to abnormal brain development and muscle abnormality, analogous to phenotypes observed in individuals carrying GMPPA or GMPPB mutations. We conclude that GMPPA acts as a cellular sensor to maintain mannose homeostasis through allosterically regulating GMPPB.”(Abstract)
Fig. 2:GMPPA and GMPPB regulate neuronal and muscle development in zebrafish by controlling GDP-Man concentration.
These two studies provide important basis for clinical diagnosis and treatment of congenital glycosylation diseases.
Da Jia, a professor and doctoral students advisor of the State Key Laboratory of Biotherapy, West China Second University Hospital, SCU, is a young national high-level expert. His research group employs a combination of methods involving cell biology, biochemistry, proteomics, model animals (zebrafish and mice) to answer the questions about vesicle transport and pathogenesis of related diseases, and to explore their treatment. A total of 38 SCI papers have been published and cited more than 4,000 times. He joined Sichuan University in October 2015 and has published papers in JCB, NSMB, PNAS,Nature Communications,PLoS Biology,STTT, Molecular Biomedicine, JBC as a corresponding author or co-corresponding author. In 2018, the research results of his research group were selected as the "Top Ten Basic Science Progress" of Sichuan University.
https://www.nature.com/articles/s41594-021-00591-9;
https://link.springer.com/article/10.1186/s43556-021-00027-2#author-information)
