TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

Jemeen Sreedharan; Ian P. Blair; Vineeta B. Tripathi; Xun Hu; Caroline Vance; Boris Rogelj; Steven Ackerley; Jennifer C. Durnall; Kelly L. Williams; Emanuele Buratti; Francisco Baralle; Jacqueline De Belleroche; J. Douglas Mitchell; P. Nigel Leigh; Ammar Al-Chalabi; Christopher C. Miller; Garth Nicholson; Christopher E. Shaw

doi:10.1126/science.1154584

TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

Jemeen Sreedharan, Ian P. Blair, Vineeta B. Tripathi, Xun Hu, Caroline Vance, Boris Rogelj, Steven Ackerley, Jennifer C. Durnall, Kelly L. Williams, Emanuele Buratti, Francisco Baralle, Jacqueline De Belleroche, J. Douglas Mitchell, P. Nigel Leigh, Ammar Al-Chalabi, Christopher C. Miller, Garth Nicholson, Christopher E. Shaw

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

2204 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBP_M337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

Original language	English
Pages (from-to)	1668-1672
Number of pages	5
Journal	Science
Volume	319
Issue number	5870
DOIs	https://doi.org/10.1126/science.1154584
Publication status	Published - 21 Mar 2008
Externally published	Yes

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Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., Baralle, F., De Belleroche, J., Mitchell, J. D., Leigh, P. N., Al-Chalabi, A., Miller, C. C., Nicholson, G., & Shaw, C. E. (2008). TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science, 319(5870), 1668-1672. https://doi.org/10.1126/science.1154584

@article{7258f12e60cc475192222ab91ea18307,

title = "TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis",

abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.",

author = "Jemeen Sreedharan and Blair, {Ian P.} and Tripathi, {Vineeta B.} and Xun Hu and Caroline Vance and Boris Rogelj and Steven Ackerley and Durnall, {Jennifer C.} and Williams, {Kelly L.} and Emanuele Buratti and Francisco Baralle and {De Belleroche}, Jacqueline and Mitchell, {J. Douglas} and Leigh, {P. Nigel} and Ammar Al-Chalabi and Miller, {Christopher C.} and Garth Nicholson and Shaw, {Christopher E.}",

year = "2008",

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day = "21",

doi = "10.1126/science.1154584",

language = "English",

volume = "319",

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Sreedharan, J, Blair, IP, Tripathi, VB, Hu, X, Vance, C, Rogelj, B, Ackerley, S, Durnall, JC, Williams, KL, Buratti, E, Baralle, F, De Belleroche, J, Mitchell, JD, Leigh, PN, Al-Chalabi, A, Miller, CC, Nicholson, G & Shaw, CE 2008, 'TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis', Science, vol. 319, no. 5870, pp. 1668-1672. https://doi.org/10.1126/science.1154584

TY - JOUR

T1 - TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

AU - Sreedharan, Jemeen

AU - Blair, Ian P.

AU - Tripathi, Vineeta B.

AU - Hu, Xun

AU - Vance, Caroline

AU - Rogelj, Boris

AU - Ackerley, Steven

AU - Durnall, Jennifer C.

AU - Williams, Kelly L.

AU - Buratti, Emanuele

AU - Baralle, Francisco

AU - De Belleroche, Jacqueline

AU - Mitchell, J. Douglas

AU - Leigh, P. Nigel

AU - Al-Chalabi, Ammar

AU - Miller, Christopher C.

AU - Nicholson, Garth

AU - Shaw, Christopher E.

PY - 2008/3/21

Y1 - 2008/3/21

N2 - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

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U2 - 10.1126/science.1154584

DO - 10.1126/science.1154584

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C2 - 18309045

AN - SCOPUS:41149180753

SN - 0036-8075

VL - 319

SP - 1668

EP - 1672

JO - Science

JF - Science

IS - 5870

ER -

TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

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