Role of myeloperoxidase-mediated neuroinflammation in aceruloplasminemia

Aceruloplasminemia is an ultra-rare genetic disease characterized by lack or inactivation of the ferroxidase enzyme ceruloplasmin. The disorder is characterized by brain iron accumulation and neurodegeneration, but the mechanisms underlying neuronal death are poorly understood. Nowadays no therapy is available. In addition to enzymatic activity, ceruloplasmin has another non-enzymatic function, namely inhibition of myeloperoxidase a protein that mediated neuroinflammation. In the mouse model of the disease we demonstrated that the therapeutic administration of purified ceruloplasmin was efficacious in ameliorating neurological symptoms. Now, our preliminary studies show that the murine model display neuroinflammation and that ceruloplasmin treatment reverts the neuroinflammatory phenotype. Thus, we hypothesized that in the absence of ceruloplasmin, increased myeloperoxidase activity and neuroinflammation may be responsible for early neuronal damage.

In this project we will study in the mouse model the occurrence of neuroinflammation along disease progression from early stages to overt neurodegeneration. In the brain of these mice we will investigate the myeloperoxidase’s expression level and activity and will correlate them with neuroinflammation and/or neurodegeneration. The aim is to define the role of the myeloperoxidase-mediated neuroinflammation as early pathological mechanism in aceruloplasminemia, that may lead to novel therapeutic strategies. Furthermore, to determine the relative importance of ceruloplasmin’s ferroxidase activity and its myeloperoxidase-inhibition function in exerting therapeutic effect, recombinant ceruloplasmin and recombinant ceruloplasmin-mutants in which the myeloperoxidase-inhibitory function is abolished without altering ferroxidase-enzymatic activity, or vice-versa, will be produced and employed for protein-replacement therapy in the mouse model of the disease, examining the efficacy in mitigating neuroinflammation and/or neurodegeneration.