The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice

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 <i>IREB2</i> 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 <i>IREB2</i>-mutated animal model has left the underlying pathogenic mechanisms poorly understood. To investigate this, we establish a CRISPR-Cas9-mediated <i>Ireb2</i> ^D826V/D826V mouse model, which carries the c.2477A>T (p.D826V) pathogenic variant in <i>IREB2</i> 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 <i>Ireb2</i> ^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, <i>Ireb2</i> ^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 <i>Ireb2</i> ^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.