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

TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

Jemeen Sreedharan ¹, Ian P. Blair ², Vineeta B. Tripathi ¹, 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, Christopher E. Shaw ^1*

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

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. 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 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.