Ceruloplasmin in neurodegenerative diseases.
For decades, abnormalities in ceruloplasmin (Cp) synthesis have been associated with neurodegenerative disease. From the early observation that low circulating serum ceruloplasmin levels served as a marker for Wilson's disease to the recent characterization of a neurodegenerative disorder associated with a complete lack of serum ceruloplasmin, the link between Cp and neuropathology has strengthened. The mechanisms associated with these different central nervous system abnormalities are very distinct. In Wilson's disease, a defect in the P-type ATPase results in abnormal hepatic copper accumulation that eventually leaks into the circulation and is abnormally deposited in the brain. In this case, copper deposition results in the neurodegenerative phenotype observed. Patients with autosomal recessive condition, aceruloplasminemia, lack the ferroxidase activity inherent to the multi-copper oxidase ceruloplasmin and develop abnormal iron accumulation within the central nervous system. In the following review ceruloplasmin gene expression, structure and function will be presented and the role of ceruloplasmin in iron metabolism will be discussed. The molecular events underlying the different forms of neurodegeneration observed will be presented. Understanding the role of ceruloplasmin within the central nervous system is fundamental to further our understanding of the pathology observed. Is the ferroxidase function more essential than the antioxidant role? Does Cp help maintain nitrosothiol stores or does it oxidize critical brain substrates? The answers to these questions hold the promise for the treatment of devastating neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. It is essential to further elucidate the mechanism of the neuronal injury associated with these disorders.
Vassiliev
Vadim
V
Institute for Experimental Medicine, St. Petersburg, Russia.
Harris
Zena Leah
ZL
Zatta
Paolo
P
D000818:Animals; D002570:Ceruloplasmin / Q000235:genetics / Q000502:physiology*; D003300:Copper / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007501:Iron / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000503:physiopathology*; D013329:Structure-Activity Relationship
D003300:Copper; D007501:Iron; D002570:Ceruloplasmin