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

TitleAxonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations.
Publication TypeJournal Article
Year of Publication2014
AuthorsAlami 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, J Taylor P
JournalNeuron
Volume81
Issue3
Pagination536-43
Date Published2014 Feb 5
ISSN1097-4199
KeywordsAmyotrophic 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
Abstract

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.

DOI10.1016/j.neuron.2013.12.018
Alternate JournalNeuron
PubMed ID24507191
PubMed Central IDPMC3939050
Grant List089701 / / Wellcome Trust / United Kingdom
8DP1NS082099 / DP / NCCDPHP CDC HHS / United States
AG031587 / AG / NIA NIH HHS / United States
NS053825 / NS / NINDS NIH HHS / United States
P30 CA021765-34 / CA / NCI NIH HHS / United States
R01 NS053825 / NS / NINDS NIH HHS / United States
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