title: Misregulation of human sortilin splicing leads to the generation of a nonfunctional progranulin receptor.
abstract: 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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Prudencio
authors.forename: Karen R
authors.initials: KR
authors.lastname: Jansen-West
authors.forename: Wing C
authors.initials: WC
authors.lastname: Lee
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Xu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gass
authors.forename: Cristiana
authors.initials: C
authors.lastname: Stuani
authors.forename: Caroline
authors.initials: C
authors.lastname: Stetler
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Emanuele
authors.initials: E
authors.lastname: Buratti
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005091:Exons / Q000235:genetics; D005998:Glycine / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D000077153:Progranulins; D011485:Protein Binding; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012326:RNA Splicing / Q000235:genetics*; D013329:Structure-Activity Relationship; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D005998:Glycine; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D020033:Protein Isoforms; D000099183:Sortilin; C492314:GRN protein, human