Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations

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• 作者：Nael聽H. Alami ; Rebecca聽B. Smith ; Monica聽A. Carrasco ; Luis聽A. Williams ; Christina聽S. Winborn ; Steve聽S.W. Han ; Evangelos Kiskinis ; Brett Winborn ; Brian聽D. Freibaum ; Anderson Kanagaraj ; Alison聽J. Clare ; Nisha聽M. Badders ; Bilada Bilican ; Edward Chaum ; Siddharthan Ch ; ran ; Christopher聽E. Shaw ; Kevin聽C. Eggan ; Tom Maniatis ; J.聽Paul Taylor
• 刊名：Neuron
• 出版年：5 February, 2014
• 年：2014
• 卷：81
• 期：3
• 页码：536-543
• 全文大小：1915 K

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Summary

The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a聽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聽undergo bidirectional, microtubule-dependent transport in neurons in聽vitro and in聽vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in聽vivo and in聽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.