Therapeutic potential of ceruloplasmin administration in aceruloplasminemia

The aceruloplasminemia is an adult-onset hereditary disease caused by mutations in the ceruloplasmin gene that codify for a protein able to oxidize iron. Due to this specific activity, the protein ceruloplasmin plays a critical role in iron metabolism and homeostasis, avoiding dangerous intracellular iron accumulation. The complete absence of ceruloplasmin activity promotes iron deposition, which in turn induces several symptoms including involuntary movements, parkinsonism, depression and cognitive dysfunctions accompanied by retinal degeneration, diabetes, and iron-refractory anemia. The neurological symptoms are due to neurodegeneration fostered by brain iron accumulation during the disease progression. Current therapies based on iron displacement by chemical compound and human plasma administration, are efficacious in controlling liver iron deposition and anemia, but are few or ineffective on neurological symptoms. In this project we planned to investigate the therapeutic potential of ceruloplasmin protein administration in reducing neurodegeneration and in ameliorate the neurological symptoms in aceruloplasminemia. The idea is that a direct replace of the missing protein could be more effective than therapies based on the reduction of the effect produced by its absence. To this aim we will use an already characterized mouse model in which the ceruloplasmin gene is inactivated. These mice, that show aceruloplasminemia features including the neurological alterations, will be treated with ceruloplasmin, which has been recently demonstrated to be able to cross the barrier systems separating the brain from the rest of the body, thus becoming effective in the central nervous system. The treated animals will be evaluated in comparison to untreated mice for amelioration of motor symptoms, for the rescue of brain ferroxidase activity, reduction of brain iron deposition and neuronal loss.