The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations
| Autor: | Anu Jalanko, Claudia Heine, Mia-Lisa Schmiedt, Aija Kyttälä, Carlos Bessa, Maria Gil Ribeiro |
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| Rok vydání: | 2010 |
| Předmět: |
DNA
Complementary Batten disease DNA Mutational Analysis Biology medicine.disease_cause Models Biological Neuronal Ceroid-Lipofuscinoses Chlorocebus aethiops Genetics medicine Animals Humans Lysosome-associated membrane glycoprotein Gene Genetics (clinical) Glycoproteins chemistry.chemical_classification Regulation of gene expression Mutation COS cells Lysosome-Associated Membrane Glycoproteins Membrane Proteins medicine.disease Recombinant Proteins Cell biology Gene Expression Regulation chemistry COS Cells Neuronal ceroid lipofuscinosis Lysosomes Glycoprotein HeLa Cells |
| Zdroj: | Human Mutation. 31:356-365 |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.21195 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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