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Science 2 May 2003:
Vol. 300. no. 5620, pp. 808 - 812
DOI: 10.1126/science.1083129
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Reports

Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport

Majid Hafezparast,1* Rainer Klocke,2* Christiana Ruhrberg,3 Andreas Marquardt,2 Azlina Ahmad-Annuar,1 Samantha Bowen,4 Giovanna Lalli,3 Abi S. Witherden,1 Holger Hummerich,1 Sharon Nicholson,1 P. Jeffrey Morgan,4 Ravi Oozageer,4 John V. Priestley,5 Sharon Averill,5 Von R. King,5 Simon Ball,6 Jo Peters,6 Takashi Toda,3 Ayumu Yamamoto,7 Yasushi Hiraoka,7 Martin Augustin,2 Dirk Korthaus,2 Sigrid Wattler,2 Philipp Wabnitz,2 Carmen Dickneite,2 Stefan Lampel,2 Florian Boehme,2 Gisela Peraus,2 Andreas Popp,2 Martina Rudelius,8 Juergen Schlegel,8 Helmut Fuchs,9 Martin Hrabe de Angelis,9 Giampietro Schiavo,3 David T. Shima,3{dagger} Andreas P. Russ,2 Gabriele Stumm,2{ddagger} Joanne E. Martin,4 Elizabeth M. C. Fisher1{ddagger}

Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.

1 Department of Neurodegenerative Disease, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
2 Ingenium Pharmaceuticals AG, Fraunhoferstrasse 13, 82152 Martinsried, Munich, Germany.
3 Cancer Research UK, Laboratories of Endothelial Cell Biology, Cell Regulation and Molecular Neuropathobiology, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
4 Department of Histopathology, Queen Mary University of London, The Royal London Hospital, Whitechapel, London E1 1BB, UK.
5 Department of Neuroscience, Barts and The London, Queen Mary University of London, London E1 4NS, UK.
6 Medical Research Council Mammalian Genetics Unit, Harwell OX11 ORD, UK.
7 Cell Biology Group, Core Research for Evolutional Science and Technology (CREST) Research Project, Kansai Advanced Research Center, Communications Research Laboratory, Kobe 651-2492, Japan.
8 Division of Neuropathology, Institute of Pathology, Munich Technical University, Ismaninger Strasse 22, 81675 Munich, Germany.
9 Institute of Experimental Genetics at the Gesellschaft für Strahlenforschung–National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.



* These authors contributed equally to this work.

{dagger} Present address: Eyetech Pharmaceuticals, 42 Cummings Park, Woburn, MA 01801, USA.

{ddagger} To whom correspondence should be addressed. E-mail: e.fisher{at}prion.ucl.ac.uk (E.M.C.F.)

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