ANALYSIS OF THE MELANOSOMAL PROTEIN SORTING PATHWAY IN NORMAL MELANOCYTES, AS A TOOL TO UNCOVER KEY STEPS IN THE PATHOGENESIS OF OCULAR AND OCULOCUTANEOUS ALBINISMS

Melanosomes are discrete compartments (organelles) in the cytoplasm of pigmented cells in skin and eye. Within melanosomes the cells synthesize the pigment melanin. The cell has to activate a series of mechanisms to allow the transport of the necessary specific machinery (proteins) from the organelle deputed to their synthesis to the melanosome. Furthermore, this machinery involves also elements responsible for the control of the rate of maturation of the melanosome (i.e. how dark it gets). Defects in any element of the transport and function/control machinery may lead to diseases, known as albinisms. Ocular Albinism 1 (OA1), is a genetic disease characterized by the abnormal growth of the melanosomes (giant melanosomes) within the pigmented cell of skin and eye. In addition to OA1, other forms of albinisms (Hermansky-Pudlack and Chediak-Higashi syndromes) are characterized by a giant melanosome phenotype, but associated with defects in other organelles (secretory granules and lysosomes), suggesting that all these organelles have some element in common. In support of this hypothesis is the observation that melanosomes contain several proteins known to be lysosome residents. The melanosomal proteins are packaged in a compartment called Trans-Golgi Network (TGN), and from here sent to melanosomes. Our preliminary data suggest that this pathway includes intermediate steps through other compartments called endosomes, known to be also intermediate steps of traffic to lysosome. Our first aim is to define the TGN to melanosome sorting pathway, following the fate of several melanosomal proteins, including the Oa1 the product of the gene responsible for OA1. Second aim will be the evaluation of the potential role of Oa1 in the melanosome movement and the definition of the mechanisms involved. The third aim will be the identification of the role played by the Oa1 in the melanosome maturation, to identify mechanisms that could be target of pharmacological therapy.