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

Neurology

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

421 Scopus citations

Abstract

The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is amajor 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 thatundergo bidirectional, microtubule-dependent transport in neurons invitro and invivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function invivo and invitro, 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 (US)
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
State	Published - Feb 5 2014

ASJC Scopus subject areas

Neuroscience(all)

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10.1016/j.neuron.2013.12.018

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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{843b1e3fa1e843c49581d892b83c7aa7,

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 amajor 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 thatundergo bidirectional, microtubule-dependent transport in neurons invitro and invivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function invivo and invitro, 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.",

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}",

note = "Funding Information: We thank H. Mitsumoto and C. Henderson (Project A.L.S./Columbia) and R. Brown (UMass Medical School) for collection of Patient 47 and Patient RB20 material. We also thank D. Zarnescu for providing the UAS-YFP-TDP-43 (A315T) Drosophila lines and C. Gu and D. Solecki for provision of YFP-EB1 and pCIG2-GFP expression plasmids, respectively. This work was supported by grants from the Packard Foundation, Target ALS, the ALS Association, and NIH grants NS053825 and AG031587 to J.P.T., and an NIH Director{\textquoteright}s Pioneer Award to T.M. (8DP1NS082099). Images were acquired in the Cell & Tissue Imaging Center at St. Jude, which is supported by the American-Lebanese-Syrian Associated Charities and NCI P30 CA021765-34. ",

year = "2014",

month = feb,

day = "5",

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

language = "English (US)",

volume = "81",

pages = "536--543",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "3",

}

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

N1 - Funding Information: We thank H. Mitsumoto and C. Henderson (Project A.L.S./Columbia) and R. Brown (UMass Medical School) for collection of Patient 47 and Patient RB20 material. We also thank D. Zarnescu for providing the UAS-YFP-TDP-43 (A315T) Drosophila lines and C. Gu and D. Solecki for provision of YFP-EB1 and pCIG2-GFP expression plasmids, respectively. This work was supported by grants from the Packard Foundation, Target ALS, the ALS Association, and NIH grants NS053825 and AG031587 to J.P.T., and an NIH Director’s Pioneer Award to T.M. (8DP1NS082099). Images were acquired in the Cell & Tissue Imaging Center at St. Jude, which is supported by the American-Lebanese-Syrian Associated Charities and NCI P30 CA021765-34.

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 amajor 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 thatundergo bidirectional, microtubule-dependent transport in neurons invitro and invivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function invivo and invitro, 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 amajor 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 thatundergo bidirectional, microtubule-dependent transport in neurons invitro and invivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function invivo and invitro, 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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U2 - 10.1016/j.neuron.2013.12.018

DO - 10.1016/j.neuron.2013.12.018

M3 - Article

C2 - 24507191

AN - SCOPUS:84893508018

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

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