Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.

TitleLong pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.
Publication TypeJournal Article
Year of Publication2011
AuthorsPolymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling S-C, Sun E, Wancewicz E, Mazur C, Kordasiewicz H, Sedaghat Y, Donohue J P, Shiue L, Bennett FC, Yeo GW, Cleveland DW
JournalNat Neurosci
Volume14
Issue4
Pagination459-68
Date Published2011 Apr
ISSN1546-1726
Keywords3' Untranslated Regions, Alternative Splicing, Amyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, Female, Homeostasis, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Neurons, Oligonucleotides, Antisense, RNA Precursors, RNA, Messenger
Abstract

We used cross-linking and immunoprecipitation coupled with high-throughput sequencing to identify binding sites in 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein that, when mutated, causes amyotrophic lateral sclerosis. Massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs were changed (including Fus (Tls), progranulin and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events were detected (including in sortilin, the receptor for progranulin) following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides. RNAs whose levels were most depleted by reduction in TDP-43 were derived from genes with very long introns and that encode proteins involved in synaptic activity. Lastly, we found that TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation.

DOI10.1038/nn.2779
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/21358643?dopt=Abstract
PMCPMC3094729
Alternate JournalNat. Neurosci.
PubMed ID21358643