Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.
|Title||Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Polymenidou 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|
|Date Published||2011 Apr|
|Keywords||3' 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|
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.
|Alternate Journal||Nat. Neurosci.|