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Neuron DOI:10.1016/j.neuron.2013.12.018

Axonal 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
Pages536-543
Date Published2014 Feb 05
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
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24507191?dopt=Abstract

Alternate JournalNeuron
PubMed ID24507191
PubMed Central IDPMC3939050
Grant ListNS053825 / 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