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Published Online February 28, 2008
Science DOI: 10.1126/science.1154584

Reports

Submitted on December 26, 2007
Accepted on February 19, 2008

TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

Jemeen Sreedharan 1{dagger}, Ian P. Blair 2{dagger}, Vineeta B. Tripathi 1{dagger}, Xun Hu 1, Caroline Vance 1, Boris Rogelj 1, Steven Ackerley 3, Jennifer C. Durnall 4, Kelly L. Williams 4, 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 3, Garth Nicholson 8{dagger}, Christopher E. Shaw 1{dagger}*

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 Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, 2137, Australia.; Faculty of Medicine, University of Sydney, NSW, 2139, Australia.
3 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.
4 Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, 2137, 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 Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, 2137, Australia.; Faculty of Medicine, University of Sydney, NSW, 2139, Australia.; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, 2139, Australia.

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

{dagger}These authors contributed equally to this work.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterised 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 neighbouring 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 more readily than wild-type in vitro and caused neural apoptosis and developmental delay in the chick embryo in vivo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.


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