Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations.
Neuron
; 81(3): 536-543, 2014 Feb 05.
Article
em En
| MEDLINE
| ID: mdl-24507191
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transporte Axonal
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RNA Mensageiro
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Proteínas de Ligação a DNA
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Esclerose Lateral Amiotrófica
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Neurônios Motores
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Mutação
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article