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. 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.