title: Progranulin transcripts with short and long 5' untranslated regions (UTRs) are differentially expressed via posttranscriptional and translational repression.
abstract: Frontotemporal lobar degeneration is associated with cytoplasmic or nuclear deposition of the TAR DNA-binding protein 43 (TDP-43). Haploinsufficiency of progranulin (GRN) is a major genetic risk factor for frontotemporal lobar degeneration associated with TDP-43 deposition. Therefore, understanding the mechanisms that control cellular expression of GRN is required not only to understand disease etiology but also for the development of potential therapeutic strategies. We identified different GRN transcripts with short (38-93 nucleotides) or long (219 nucleotides) 5' UTRs and demonstrate a cellular mechanism that represses translation of GRN mRNAs with long 5' UTRs. The long 5' UTR of GRN mRNA contains an upstream open reading frame (uORF) that is absent in all shorter transcripts. Because such UTRs can be involved in translational control as well as in mRNA stability, we compared the expression of GRN in cells expressing cDNAs with and without 5' UTRs. This revealed a selective repression of GRN translation and a reduction of mRNA levels by the 219-nucleotide-long 5' UTR. The specific ability of this GRN 5' UTR to repress protein expression was further confirmed by its transfer to an independent reporter. Deletion analysis identified a short stretch between nucleotides 76 and 125 containing two start codons within one uORF that is required and sufficient for repression of protein expression. Mutagenesis of the two AUG codons within the uORF is sufficient to reduce translational repression. Therefore initiating ribosomes at the AUGs of the uORF fail to efficiently initiate translation at the start codon of GRN. In parallel the 5' UTR also affects mRNA stability; thus two independent mechanisms determine GRN expression via mRNA stability and translational efficiency.
authors: From the Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany, anja.capell@mail03.med.uni-muenchen.de.
authors: Anja
authors: A
authors: Capell
authors: From the Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany.
authors: Katrin
authors: K
authors: Fellerer
authors: From the Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians University Munich, 80336 Munich, Germany, the German Center for Neurodegenerative Diseases (DZNE), 80336 Munich, Germany, and the Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany christian.haass@mail03.med.uni-muenchen.de.
authors: Christian
authors: C
authors: Haass
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D016366:Open Reading Frames; D010443:Peptide Chain Termination, Translational / Q000235:genetics*; D000077153:Progranulins; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D020033:Protein Isoforms; D012333:RNA, Messenger
keywords: Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig Disease); Frontotemporal Lobar Degeneration; Neurodegeneration; Neurodegenerative Disease; Neuroinflammation; Progranulin; Protein Expression; TAR DNA Binding Protein 43; Translational Control