Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal ceroid lipofuscinoses are a group of diseases characterized by accumulation of hydrophobic proteins in lysosomes of neurons and other types of cells. NCLs are caused by at least 8 mutant genes (CLN1-CLN8), though CLN4 and CLN7 have not yet been identified. Except for Cln1p, the protein encoded by CLN1, the defective proteins are associated with lysosomal accumulation of mitochondrial ATP synthase subunit c. Cln1p and Cln2p are soluble lysosomal enzymes, targeted to lysosomes in a mannose 6-phosphate dependent manner. Mutations in the lysosomal protease cathepsin D cause another NCL. Cln3p, Cln5p, Cln6p and Cln8p are thought to be transmembrane proteins. Cln3p and Cln5p are localized in the endosome-lysosomal compartment. Deficiency of endosomal membrane protein CLC-3, a member of the chloride channel family, causes NCL-like phenotype and lysosomal storage of subunit c. Herein, we review the features of NCL and NCL-related proteins and discuss the involvement of the proteins in lysosomal degradation of subunit c.
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PMID:The intracellular location and function of proteins of neuronal ceroid lipofuscinoses. 1499 40

Neuronal ceroid lipofuscinoses (NCL) are caused by mutations in eight different genes, are characterized by lysosomal accumulation of autofluorescent storage material, and result in a disease that causes degeneration of the central nervous system (CNS). Although functions are defined for some of the soluble proteins that are defective in NCL (cathepsin D, PPT1, and TPP1), the primary function of the other proteins defective in NCLs (CLN3, CLN5, CLN6, CLN7, and CLN8) remain poorly defined. Understanding the localization and network of interactions for these proteins can offer clues as to the function of the NCL proteins and also the pathways that will be disrupted in their absence. Here, we present a review of the current understanding of the localization, interactions, and function of the proteins associated with NCL.
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PMID:Interactions of the proteins of neuronal ceroid lipofuscinosis: clues to function. 2068 Mar 90

The fatal, primarily childhood neurodegenerative disorders, neuronal ceroid lipofuscinoses (NCLs), are currently associated with mutations in 13 genes. The protein products of these genes (CLN1 to CLN14) differ in their function and their intracellular localization. NCL-associated proteins have been localized mostly in lysosomes (CLN1, CLN2, CLN3, CLN5, CLN7, CLN10, CLN12 and CLN13) but also in the Endoplasmic Reticulum (CLN6 and CLN8), or in the cytosol associated to vesicular membranes (CLN4 and CLN14). Some of them such as CLN1 (palmitoyl protein thioesterase 1), CLN2 (tripeptidyl-peptidase 1), CLN5, CLN10 (cathepsin D), and CLN13 (cathepsin F), are lysosomal soluble proteins; others like CLN3, CLN7, and CLN12, have been proposed to be lysosomal transmembrane proteins. In this review, we give our views and attempt to summarize the proposed and confirmed functions of each NCL protein and describe and discuss research results published since the last review on NCL proteins. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".
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PMID:Cell biology of the NCL proteins: What they do and don't do. 2596 10

The neuronal ceroid lipofuscinoses (NCLs) are a family of neurodegenerative diseases that affect people of all ages and ethnicities, yet many of the associated genes/proteins are not well characterized. Mutations in MFSD8 (major facilitator superfamily domain-containing 8) cause an infantile form of NCL referred to as CLN7 disease. In this study, we revealed the localization and binding partners of an ortholog of human MFSD8 (Mfsd8) in the social amoeba Dictyostelium discoideum. Putative lysosomal targeting motifs are conserved in Dictyostelium Mfsd8, as are several residues mutated in CLN7 disease patients. Mfsd8 tagged with GFP localizes to endocytic compartments, which includes acidic intracellular vesicles and late endosomes. We pulled-down GFP-Mfsd8 and used mass spectrometry to reveal the Mfsd8 interactome during Dictyostelium growth and starvation. Among the identified hits were the Dictyostelium ortholog of human cathepsin D (CtsD), as well as proteins linked to the functions of the CLN3 (Cln3) and CLN5 (Cln5) orthologs in Dictyostelium. To study the function of Mfsd8, we validated a publically available mfsd8- cell line (GWDI Project) and then used this knockout cell line to show that Mfsd8 influences the secretion of Cln5 and CtsD. This information is then integrated into an emerging model describing the molecular networking of NCL proteins in Dictyostelium. In total, this study identifies Dictyostelium as a new model system for studying CLN7 disease.
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PMID:Mfsd8 localizes to endocytic compartments and influences the secretion of Cln5 and cathepsin D in Dictyostelium. 3208 3