The RhoB p.S73F mutation leads to cerebral palsy through dysregulation of lipid homeostasis.

Autor:	Wu X; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China., Liu R; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China., Zhang Z; CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.; Sanya Institute of Swine Resource, Hainan Provincial Research Centre of Laboratory Animals, Sanya, 572000, China.; Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen, 529020, China.; Jilin Provincial Key Laboratory of Animal Embryo Engineering, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, China.; Institute of Stem Cells and Regeneration, Chinese Academy of Sciences, Beijing, 100039, China.; Research Unit of Generation of Large Animal Disease Models, Chinese Academy of Medical Sciences, Guangzhou, 510530, China., Yang J; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China., Liu X; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China., Jiang L; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China., Fang M; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China., Wang S; School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong., Lai L; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China. lai_liangxue@gibh.ac.cn.; CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. lai_liangxue@gibh.ac.cn.; Sanya Institute of Swine Resource, Hainan Provincial Research Centre of Laboratory Animals, Sanya, 572000, China. lai_liangxue@gibh.ac.cn.; Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen, 529020, China. lai_liangxue@gibh.ac.cn.; Jilin Provincial Key Laboratory of Animal Embryo Engineering, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, China. lai_liangxue@gibh.ac.cn.; Institute of Stem Cells and Regeneration, Chinese Academy of Sciences, Beijing, 100039, China. lai_liangxue@gibh.ac.cn.; Research Unit of Generation of Large Animal Disease Models, Chinese Academy of Medical Sciences, Guangzhou, 510530, China. lai_liangxue@gibh.ac.cn., Song Y; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China. songyuning0313@jlu.edu.cn., Li Z; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China. lizj_1998@jlu.edu.cn.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2024 Sep; Vol. 16 (9), pp. 2002-2023. Date of Electronic Publication: 2024 Jul 30.
DOI:	10.1038/s44321-024-00113-2
Abstrakt:	Cerebral palsy (CP) is a prevalent neurological disorder that imposes a significant burden on children, families, and society worldwide. Recently, the RhoB p.S73F mutation was identified as a de novo mutation associated with CP. However, the mechanism by which the RhoB p.S73F mutation causes CP is currently unclear. In this study, rabbit models were generated to mimic the human RhoB p.S73F mutation using the SpG-BE4max system, and exhibited the typical symptoms of human CP, such as periventricular leukomalacia and spastic-dystonic diplegia. Further investigation revealed that the RhoB p.S73F mutation could activate ACAT1 through the LYN pathway, and the subsequently altered lipid levels may lead to neuronal and white matter damage resulting in the development of CP. This study presented the first mammalian model of genetic CP that accurately replicates the RhoB p.S73F mutation in humans, provided further insights between RhoB and lipid metabolism, and novel therapeutic targets for human CP. (© 2024. The Author(s).)
Databáze:	MEDLINE
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