期刊
NEURON
卷 81, 期 3, 页码 536-543出版社
CELL PRESS
DOI: 10.1016/j.neuron.2013.12.018
关键词
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资金
- Packard Foundation
- Target ALS
- ALS Association
- NIH [NS053825, AG031587, 8DP1NS082099]
- Medical Research Council [G0900688, MC_G1000733, G1100695, G0300329, G0501573, G0500289B, G0600974, G0500289, G0900635] Funding Source: researchfish
- MRC [G0900635, G0900688, MC_G1000733, G0501573, G0500289, G0600974, G0300329, G1100695] Funding Source: UKRI
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.
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