Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations

Nael H. Alami, Rebecca B. Smith, Monica A. Carrasco, Luis A. Williams, Christina S. Winborn, Steve S W Han, Evangelos Kiskinis, Brett Winborn, Brian D. Freibaum, Anderson Kanagaraj, Alison J. Clare, Nisha M. Badders, Bilada Bilican, Edward Chaum, Siddharthan Chandran, Christopher E. Shaw, Kevin C. Eggan, Tom Maniatis, J. Paul Taylor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

421 Scopus citations


The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is amajor 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 thatundergo bidirectional, microtubule-dependent transport in neurons invitro and invivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function invivo and invitro, 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.

Original languageEnglish (US)
Pages (from-to)536-543
Number of pages8
Issue number3
StatePublished - Feb 5 2014

ASJC Scopus subject areas

  • Neuroscience(all)


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