The D826V point mutation in IREB2 causes early-onset neurodegeneration in miceOA
The iron regulatory protein IREB2(Iron Responsive Element Binding Protein 2)plays a crucial role in maintaining cellular iron homeostasis through the posttranscriptional regulation of genes involved in iron metabolism.Mutations in the IREB2 gene have been linked to NDCAMA(OMIM#618451),a rare genetic neurological disorder characterized by early-onset neurodegeneration,choreoathetoid movements,and microcytic anemia.However,the absence of an IREB2-mutated animal model has left the underlying pathogenic mechanisms poorly understood.To investigate this,we establish a CRISPR-Cas9-mediated Ireb2^(D826v/D826V) mouse model,which carries the c.2477A>T(p.D826V)pathogenic variant in IREB2 identified in a Chinese pedigree with NDCAMA.Behavioral studies,including the Morris water maze(MWM),open field test(OFT),and Y-maze,reveal significant neurobehavioral deficits,such as impaired spatial learning and memory and reduced motor activity,in Ireb2^(D826v/D826v) mice.Furthermore,we observe increased microglial activation and decreased dendritic spine density in the hippocampus,along with impaired long-term potentiation(LTP)and elevated paired-pulse facilitation(PPF),indicating synaptic dysfunction.Mechanistically,Ireb2^(D826v/D826V) mice present reduced Ireb2 protein levels,dysregulated iron metabolism,and an altered expression profile associated with neurological function.This study elucidates the molecular mechanisms underlying NDCAMA and establishes Ireb2^(D826v/D826V) mice as a model for iron metabolism-driven neurodegeneration.This finding links the instability of IREB2 to synaptic failure and neuroinflammation,highlighting potential therapeutic implications for neurodegenerative diseases.
Zhenglong Guo;Yibing Lv;Jianmei Huang;Yingying Shao;Yuwei Zhang;Yibin Hao;Bingtao Hao;Zhenbo Cheng;Shixiu Liao
Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics&Medical Genetics Institute of Henan Province,Henan Provincial People''s Hospital,People''s Hospital of Zhengzhou University,Zhengzhou 450003,China School of Medicine,People''s Hospital of Henan University,Henan University,Zhengzhou 450003,ChinaHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics&Medical Genetics Institute of Henan Province,Henan Provincial People''s Hospital,People''s Hospital of Zhengzhou University,Zhengzhou 450003,China School of Medicine,People''s Hospital of Henan University,Henan University,Zhengzhou 450003,ChinaHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics&Medical Genetics Institute of Henan Province,Henan Provincial People''s Hospital,People''s Hospital of Zhengzhou University,Zhengzhou 450003,China School of Medicine,People''s Hospital of Henan University,Henan University,Zhengzhou 450003,ChinaThe First Affiliated Hospital of Zhengzhou University,Zhengzhou 450000,ChinaHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics&Medical Genetics Institute of Henan Province,Henan Provincial People''s Hospital,People''s Hospital of Zhengzhou University,Zhengzhou 450003,China School of Medicine,People''s Hospital of Henan University,Henan University,Zhengzhou 450003,ChinaHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics&Medical Genetics Institute of Henan Province,Henan Provincial People''s Hospital,People''s Hospital of Zhengzhou University,Zhengzhou 450003,China School of Medicine,People''s Hospital of Henan University,Henan University,Zhengzhou 450003,ChinaDepartment of Immunology,School of Basic Medical,Zhengzhou University,Zhengzhou 450001,China Eye Institute,Henan Academy of Innovations in Medical Science,Zhengzhou 450000,ChinaDepartment of Clinical Laboratory,Hunan Provincial People''s Hospital,The First Affiliated Hospital of Hunan Normal University,Hunan Normal University,Changsha 410021,ChinaHenan Provincial Key Laboratory of Genetic Diseases and Functional Genomics&Medical Genetics Institute of Henan Province,Henan Provincial People''s Hospital,People''s Hospital of Zhengzhou University,Zhengzhou 450003,China School of Medicine,People''s Hospital of Henan University,Henan University,Zhengzhou 450003,China
医药卫生
IREB2NDCAMAneurodegenerationiron metabolism
《Acta Biochimica et Biophysica Sinica》 2026 (6)
P.1413-1422,10
supported by the grants from the National Natural Science Foundation of China(No.32300627 to Z.G.,82371864 to S.L.,82301882 to Z.C.)the Natural Science Foundation of Henan Province(No.232300421281 to Z.G.,232300421121 to S.L.)the Natural Science Foundation of Hunan Province(No.2025JJ50583 to Z.C.)the Major Projects Jointly Constructed by Henan Province and the Ministry of Science and Technology(No.SBGJ202101003 to S.L.)the Young Talents of Health Science and Technology Innovation in Henan Province(No.YQRC2023010 to Z.G.).
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