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

Nael H. Alami; Rebecca B. Smith; Monica A. Carrasco; Luis A. Williams; Christina S. Winborn; Steve S. W. Han; Evangelos Kiskinis; Brett Winborn; Brian D. Freibaum; Anderson Kanagaraj; Alison J. Clare; Nisha M. Badders; Bilada Bilican; Edward Chaum; Siddharthan Chandran; Christopher E. Shaw; Kevin C. Eggan; Tom Maniatis; J. Paul Taylor

doi:10.1016/j.neuron.2013.12.018

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

Nael H. Alami, Rebecca B. Smith, Monica A. Carrasco, Luis A. Williams, Christina S. Winborn, Steve S. W. Han, Evangelos Kiskinis, Brett Winborn, Brian D. Freibaum, Anderson Kanagaraj, Alison J. Clare, Nisha M. Badders, Bilada Bilican, Edward Chaum, Siddharthan Chandran, Christopher E. Shaw, Kevin C. Eggan, Tom Maniatis, J. Paul Taylor^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	536-543
Number of pages	8
Journal	Neuron
Volume	81
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2013.12.018
Publication status	Published - 5 Feb 2014

Keywords / Materials (for Non-textual outputs)

AMYOTROPHIC-LATERAL-SCLEROSIS
PLURIPOTENT STEM-CELLS
MOTOR-NEURONS
LIVING CELLS
PROTEIN
FUS/TLS
NEURODEGENERATION
VULNERABILITY
TRANSLATION
STABILITY

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10.1016/j.neuron.2013.12.018

Siddharthan Chandran
- siddharthan.chandraned.acuk
Person: Academic: Research Active

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Alami, N. H., Smith, R. B., Carrasco, M. A., Williams, L. A., Winborn, C. S., Han, S. S. W., Kiskinis, E., Winborn, B., Freibaum, B. D., Kanagaraj, A., Clare, A. J., Badders, N. M., Bilican, B., Chaum, E., Chandran, S., Shaw, C. E., Eggan, K. C., Maniatis, T., & Taylor, J. P. (2014). Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations. Neuron, 81(3), 536-543. https://doi.org/10.1016/j.neuron.2013.12.018

@article{225cdf42da18467a9ec0e00940a8acca,

title = "Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations",

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.",

keywords = "AMYOTROPHIC-LATERAL-SCLEROSIS, PLURIPOTENT STEM-CELLS, MOTOR-NEURONS, LIVING CELLS, PROTEIN, FUS/TLS, NEURODEGENERATION, VULNERABILITY, TRANSLATION, STABILITY",

author = "Alami, {Nael H.} and Smith, {Rebecca B.} and Carrasco, {Monica A.} and Williams, {Luis A.} and Winborn, {Christina S.} and Han, {Steve S. W.} and Evangelos Kiskinis and Brett Winborn and Freibaum, {Brian D.} and Anderson Kanagaraj and Clare, {Alison J.} and Badders, {Nisha M.} and Bilada Bilican and Edward Chaum and Siddharthan Chandran and Shaw, {Christopher E.} and Eggan, {Kevin C.} and Tom Maniatis and Taylor, {J. Paul}",

year = "2014",

month = feb,

day = "5",

doi = "10.1016/j.neuron.2013.12.018",

language = "English",

volume = "81",

pages = "536--543",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

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}

Alami, 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 & Taylor, JP 2014, 'Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations', Neuron, vol. 81, no. 3, pp. 536-543. https://doi.org/10.1016/j.neuron.2013.12.018

TY - JOUR

T1 - Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations

AU - Alami, Nael H.

AU - Smith, Rebecca B.

AU - Carrasco, Monica A.

AU - Williams, Luis A.

AU - Winborn, Christina S.

AU - Han, Steve S. W.

AU - Kiskinis, Evangelos

AU - Winborn, Brett

AU - Freibaum, Brian D.

AU - Kanagaraj, Anderson

AU - Clare, Alison J.

AU - Badders, Nisha M.

AU - Bilican, Bilada

AU - Chaum, Edward

AU - Chandran, Siddharthan

AU - Shaw, Christopher E.

AU - Eggan, Kevin C.

AU - Maniatis, Tom

AU - Taylor, J. Paul

PY - 2014/2/5

Y1 - 2014/2/5

N2 - 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.

AB - 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.

KW - AMYOTROPHIC-LATERAL-SCLEROSIS

KW - PLURIPOTENT STEM-CELLS

KW - MOTOR-NEURONS

KW - LIVING CELLS

KW - PROTEIN

KW - FUS/TLS

KW - NEURODEGENERATION

KW - VULNERABILITY

KW - TRANSLATION

KW - STABILITY

U2 - 10.1016/j.neuron.2013.12.018

DO - 10.1016/j.neuron.2013.12.018

M3 - Article

SN - 0896-6273

VL - 81

SP - 536

EP - 543

JO - Neuron

JF - Neuron

IS - 3

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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