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Originally published in Science Express on 28 February 2008
Science 21 March 2008:
Vol. 319. no. 5870, pp. 1668 - 1672
DOI: 10.1126/science.1154584
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Reports

TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

Jemeen Sreedharan,1* Ian P. Blair,3,4* Vineeta B. Tripathi,1* Xun Hu,1 Caroline Vance,1 Boris Rogelj,1 Steven Ackerley,1,2 Jennifer C. Durnall,3 Kelly L. Williams,3 Emanuele Buratti,5 Francisco Baralle,5 Jacqueline de Belleroche,6 J. Douglas Mitchell,7 P. Nigel Leigh,1 Ammar Al-Chalabi,1 Christopher C. Miller,1,2 Garth Nicholson,3,4,8* Christopher E. Shaw1*{dagger}

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.

1 Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
2 Department of Neuroscience, King's College London, MRC Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
3 Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Concord, NSW, 2137, Australia.
4 Faculty of Medicine, University of Sydney, Sydney, NSW, 2139, Australia.
5 International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy.
6 Division of Neurosciences and Mental Health, Faculty of Medicine, Imperial College London, and Charing Cross Hospital, London, W6 8RF, UK.
7 Department of Neurology, Royal Preston Hospital, Preston, PR2 9HT, UK.
8 Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, 2139, Australia.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: chris.shaw{at}iop.kcl.ac.uk

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