The long term objective of the proposed research is to determine how vesicles are targeted to lysosomes in normal brain and in several neurological diseases. Lysosomes are acidic organelles that are enriched in hydrolases, and capable of degrading both internalized and endogenous macromolecules. Their functional importance is highlighted by the occurrence of several dozen lysosomal disorders which cause neurological damage. Throughout the cell, highly specific vesicles trafficking is essential to allow cargo to be sent to the appropriate destination. This vesicle trafficking occurs in a specific fashion by the formation of protein-protein complexes between vesicle proteins, cytosolic proteins, and target membrane proteins. The investigators have identified brain cDNA clones encoding four proteins that may responsible for vesicle trafficking to lysosomes. These are syntaxin (homologous to yeast Pep 12p) and three proteins related to n-sec1 (mammalian homologues of yeast Vps33p and Vps45p).
The specific aims are as follows: (1) determine the subcellular localization of these presumed lysosomal proteins in brain, in normal human fibroblasts, and in fibroblasts, and in fibroblasts derived from patients with neurological disorders affecting lysosome function (such as Chediak-Higashi syndrome, Niemann-Pick disease type C, and muculipidosis IV). (2) Identify syntaxin-containing protein complexes implicated in vesicle trafficking to brain lysosomes, analogous to those complexes characterized in the presynaptic nerve terminal. These studies may contribute to our understanding of the proteins that mediate vesicle trafficking to lysosomes in neurons and other cell types. Such information may be important to understand the molecular defects in a variety of neurological disorders in which intracellular transport to (or from) lysosomes is defective.
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