title: The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations.
abstract: Neuronal ceroid lipofuscinoses (NCLs) represent a group of children's inherited neurodegenerative disorders caused by mutations in at least eight different genes. Mutations in the CLN5 gene result in the Finnish variant late infantile NCL characterized by gradual loss of vision, epileptic seizures, and mental deterioration. The CLN5 gene encodes a lysosomal glycoprotein of unidentified function. In this study, we have used both transient and stable expression systems for the characterization of CLN5, focusing on the localization, processing, and intracellular trafficking. We show that CLN5 is proteolytically cleaved, and that the mature polypeptide is transported to the lysosomes. Our data provide the first evidence that soluble CLN5 protein can also undergo mannose-6-phosphate receptor-independent trafficking to the lysosomes. We studied the localization and maturation of the CLN5 carrying the previously uncharacterized vLINCL disease causing mutations in HeLa cells. All analyzed disease mutations disturb the lysosomal trafficking of the mutated CLN5 proteins. The level of lysosomal targeting does not correlate, however, to disease onset, indicating that CLN5 may also function outside lysosomes. This study furthers our understanding of the basic properties of the CLN5 protein, necessary for the characterization of the consequences of disease mutations and for the planning of future therapies for vLINCL.
authors.affiliation: National Institute for Health and Welfare (THL), Public Health Genomics Unit, Helsinki, Finland.
authors.forename: Mia-Lisa
authors.initials: ML
authors.lastname: Schmiedt
authors.forename: Carlos
authors.initials: C
authors.lastname: Bessa
authors.forename: Claudia
authors.initials: C
authors.lastname: Heine
authors.forename: Maria Gil
authors.initials: MG
authors.lastname: Ribeiro
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
authors.forename: Aija
authors.initials: A
authors.lastname: Kyttälä
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: C113332:CLN5 protein, human; D018076:DNA, Complementary; D006023:Glycoproteins; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins