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

Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS, Han SSW, Kiskinis E, Winborn B, Freibaum BD, Kanagaraj A, Clare AJ, Badders NM, Bilican B, Chaum E, Chandran S, Shaw CE, Eggan KC, Maniatis T, Taylor JP
Neuron. 2014 81 (3): 536-543

PMID: 24507191 · PMCID: PMC3939050 · DOI:10.1016/j.neuron.2013.12.018

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

MeSH Terms (20)

Amyotrophic Lateral Sclerosis Animals Animals, Genetically Modified 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

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