Axonal transport of TDP-43 mRNA granules in neurons is impaired by ALS-causing mutations

Details

• Alternative Title:
  Neuron
• Personal Author:
  Alami, Nael H. ; Smith, Rebecca B. ; Carrasco, Monica A. ; Williams, Luis A. ; Winborn, Christina S. ; Han, Steve S. W. ; Kiskinis, Evangelos ; Winborn, Brett ; Freibaum, Brian D. ; Kanagaraj, Anderson ; Clare, Alison J. ; Badders, Nisha M. ; Bilican, Bilada ; Chaum, Edward ; Chandran, Siddharthan ; Shaw, Christopher E. ; Eggan, Kevin C. ; Maniatis, Tom ; Taylor, J. Paul
• Description:
  The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.
• Subjects:
  Amyotrophic Lateral Sclerosis Animals Animals, Genetically Modified Article Axonal Transport Cells, Cultured Cerebral Cortex DNA-Binding Proteins Drosophila Drosophila Proteins Humans Kruppel-Like Transcription Factors Luminescent Proteins Mice Mitochondria Motor Neurons Mutation Octamer Transcription Factor-3 RNA, Messenger RNA-Binding Proteins SOXB1 Transcription Factors

  More +
• Source:
  Neuron. 2013; 81(3):536-543.
• Pubmed ID:
  24507191
• Pubmed Central ID:
  PMC3939050
• Document Type:
  Journal Article
• Funding:
  NS053825/NS/NINDS NIH HHS/United States ; G0300329/Medical Research Council/United Kingdom ; 089701/Wellcome Trust/United Kingdom ; G0900635/Medical Research Council/United Kingdom ; DP1 NS082099/NS/NINDS NIH HHS/United States ; MC_G1000733/Medical Research Council/United Kingdom ; P30 CA021765-34/CA/NCI NIH HHS/United States ; G0600974/Medical Research Council/United Kingdom ; AG031587/AG/NIA NIH HHS/United States ; G1100695/Medical Research Council/United Kingdom ; G0501573/Medical Research Council/United Kingdom ; R01 NS053825/NS/NINDS NIH HHS/United States ; G0500289/Medical Research Council/United Kingdom ; P30 CA021765/CA/NCI NIH HHS/United States ; G0900688/Medical Research Council/United Kingdom ; R01 AG031587/AG/NIA NIH HHS/United States ; 8DP1NS082099/DP/NCCDPHP CDC HHS/United States ; CHANDRAN/MAR10/982-797/Motor Neurone Disease Association/United Kingdom
• Volume:
  81
• Issue:
  3
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:8c1ee109f8cd61843210383c154d88c1c9aa97ec270cc25af567d3fe1e64e4e4
• Download URL:
  https://stacks.cdc.gov/view/cdc/29863/cdc_29863_DS1.pdf
• File Type:
  [PDF - 3.80 MB ]