Proceedings of the National Academy of Sciences - PNAS, 2012-12, Vol.109 (52), p.21510-21515
2012
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Misregulation of human sortilin splicing leads to the generation of a nonfunctional progranulin receptor
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2012-12, Vol.109 (52), p.21510-21515
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Sortilin 1 regulates the levels of brain progranulin (PGRN), a neurotrophic growth factor that, when deficient, is linked to cases of frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43)–positive inclusions (FTLD-TDP). We identified a specific splicing enhancer element that regulates the inclusion of a sortilin exon cassette (termed Ex17b) not normally present in the mature sortilin mRNA. This enhancer element is consistently present in sortilin RNA of mice and other species but absent in primates, which carry a premature stop codon within the Ex17b sequence. In the absence of TDP-43, which acts as a regulatory inhibitor, Ex17b is included in the sortilin mRNA. In humans, in contrast to mice, the inclusion of Ex17b in sortilin mRNA generates a truncated, nonfunctional, extracellularly released protein that binds to but does not internalize PGRN, essentially acting as a decoy receptor. Based on these results, we propose a potential mechanism linking misregulation of sortilin splicing with altered PGRN metabolism.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1211577110Titel-ID: cdi_proquest_miscellaneous_1273346869
- Format
- –
- Schlagworte
- Adaptor Proteins, Vesicular Transport - genetics, Adaptor Proteins, Vesicular Transport - metabolism, Amino Acid Motifs, Animals, Base Sequence, Binding sites, Biological Sciences, Brain, Cellular immunity, Deoxyribonucleic acid, DNA, DNA-Binding Proteins - chemistry, DNA-Binding Proteins - metabolism, Down-Regulation, Endocytosis, Enhancer Elements, Genetic - genetics, Exons, Exons - genetics, Gene expression regulation, Glycine - metabolism, HeLa cells, Humans, Intercellular Signaling Peptides and Proteins - metabolism, Messenger RNA, Mice, Models, Biological, Molecular Sequence Data, Neurochemistry, Protein Binding, Protein Biosynthesis, Protein isoforms, Protein Isoforms - genetics, Protein Isoforms - metabolism, Protein Structure, Tertiary, Receptors, RNA, RNA Splicing - genetics, RNA-protein interactions, Rodents, Splicing, Structure-Activity Relationship