Misregulation of human sortilin splicing leads to the generation of a nonfunctional progranulin receptor

Mercedes Prudencio, Karen R. Jansen-West, Wing C. Lee, Tania F. Gendron, Yong Jie Zhang, Ya Fei Xu, Jennifer Gass, Cristiana Stuani, Caroline Stetler, Rosa Rademakers, Dennis W. Dickson, Emanuele Buratti, Leonard Petrucelli

Research output: Contribution to journalArticle

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)21510-21515
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number52
DOIs
StatePublished - Dec 26 2012

Keywords

  • ALS
  • Dementia
  • Neurodegeneration

ASJC Scopus subject areas

  • General

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