Wilson's disease (WD) is a rare genetic disease of metabolism. M. Wilson is an autosomal recessive disorder, i.e mono-allele carriers of a defective mutation of the ATP7B gene do not develop any symptoms. One differentiates between a neurological and a hepatic manifestation of the disease. Mixing forms are also known. In this subproject the genetic, physiological and epidemiological characteristics of the disease is studied. The focud of pathology is on the mutated gene ATP7B, which encodes a copper transporter of the Golgi apparatus and the outer cell membrane, which regulates the cellular egress of copper ions. Mutations in ATP7B lead to a deficient function of the gene product ("Wilson protein") and consequently to a toxic enrichment of intracellular copper. A variety of ATP7B mutations are point mutations leading to retention of defectively folded Wilson protein in the endoplasmic reticulum (ER). The Wilson protein is retained in the ER and degraded at an early stage. By establishing various cellular models of M. Wilson, new therapeutic target proteins are to be identified and their pharmacological potential examined with regard to the partial or complete elimination of the degradation defect of the mutants. A possible pharmacological intervention concerns the Wilson protein as a pharmacological target protein itself. The folding behavior of mutant forms of the protein is to be improved with the aid of pharmacological chaperones by direct, specific binding of the substance in order to make the cellular transport into the Golgi network possible. Thus, restoration of cellular copper transport could be ensured.
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