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.
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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
21 March 2008
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American Association for the Advancement of Science.
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Received: 26 December 2007
Accepted: 19 February 2008
Published in print: 21 March 2008
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