Severity of Neurodegeneration Correlates with Compromise of Iron Metabolism in Mice with Iron Regulatory Protein Deficiencies

: In mammals, iron regulatory proteins 1 and 2 (IRP1 and IRP2) posttranscriptionally regulate expression of several iron metabolism proteins including ferritin and transferrin receptor. Genetically engineered mice that lack IRP2, but have the normal complement of IRP1, develop adult-onset neurodegenerative disease associated with inappropriately high expression of ferritin in degenerating neurons. Here, we report that mice that are homozygous for a targeted deletion of IRP2 and heterozygous for a targeted deletion of IRP1 (IRP1+/− IRP2−/−) develop a much more severe form of neurodegeneration, characterized by widespread axonopathy and eventually by subtle vacuolization in several areas, particularly in the substantia nigra. Axonopathy develops in white matter tracts in which marked increases in ferric iron and ferritin expression are detected. Axonal degeneration is significant and widespread before evidence for abnormalities or loss of neuronal cell bodies can be detected. Ultimately, neuronal cell bodies degenerate in the substantia nigra and some other vulnerable areas, microglia are activated, and vacuoles appear. Mice manifest gait and motor impairment at stages when axonopathy is pronounced, but neuronal cell body loss is minimal. These observations suggest that therapeutic strategies that aim to revitalize neurons by treatment with neurotrophic factors may be of value in IRP2−/− and IRP1+/− IRP2−/− mouse models of neurodegeneration.