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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.

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This publication is dedicated to the memory of Steven Ackerley, an outstanding young scientist. We thank the patients and families who have contributed to this project and to B. Coote, C. Cecere, J. Gardham, the MRC Neurodegenerative Diseases Brain Bank and the Australian Motor Neurone Disease (MND) DNA Bank for assistance in sample collection. This work was supported by grants from The Wellcome Trust; European Union contract LSHM-CT-2003-503330 (APOPIS); American ALS Association; Motor Neurone Disease Association, UK; Medical Research Council, UK; the Middlemass family; Jack Cigman; King's College Hospital Charity; the Psychiatry Research Trust of the Institute of Psychiatry; and the Motor Neurone Disease Research Institute of Australia (MNDRIA).

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Science
Volume 319 | Issue 5870
21 March 2008

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Submission history

Received: 26 December 2007
Accepted: 19 February 2008
Published in print: 21 March 2008

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Authors

Affiliations

Jemeen Sreedharan*
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Ian P. Blair*
Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Concord, NSW, 2137, Australia.
Faculty of Medicine, University of Sydney, Sydney, NSW, 2139, Australia.
Vineeta B. Tripathi*
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Xun Hu
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Caroline Vance
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Boris Rogelj
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Steven Ackerley
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Department of Neuroscience, King's College London, MRC Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Jennifer C. Durnall
Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Concord, NSW, 2137, Australia.
Kelly L. Williams
Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Concord, NSW, 2137, Australia.
Emanuele Buratti
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy.
Francisco Baralle
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy.
Jacqueline de Belleroche
Division of Neurosciences and Mental Health, Faculty of Medicine, Imperial College London, and Charing Cross Hospital, London, W6 8RF, UK.
J. Douglas Mitchell
Department of Neurology, Royal Preston Hospital, Preston, PR2 9HT, UK.
P. Nigel Leigh
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Ammar Al-Chalabi
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Christopher C. Miller
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Department of Neuroscience, King's College London, MRC Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
Garth Nicholson*
Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Concord, NSW, 2137, Australia.
Faculty of Medicine, University of Sydney, Sydney, NSW, 2139, Australia.
Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, 2139, Australia.
Christopher E. Shaw,*
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.

Notes

† To whom correspondence should be addressed. E-mail: [email protected]

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