Description: 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. Muta- tions in the IREB2 gene have been linked to NDCAMA (OMIM#618451), a rare genetic neurological disorder char- acterized 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 Ireb2D826V/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 Ireb2D826V/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, Ireb2D826V/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 Ireb2D826V/D826V mice as a model for iron metabolism-driven neurodegenera- tion. This finding links the instability of IREB2 to synaptic failure and neuroinflammation, highlighting potential therapeutic implications for neurodegenerative diseases.

Data type: Raw sequence reads

Sample scope: Multiisolate

Relevance: Medical

Release date: 2025-11-11

Last updated: 2025-11-11

Data size: 15.64GB