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PMID: 12730604 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mutations in dynein link motor neuron degeneration to defects in retrograde transport.

Science (New York, N.Y.) ·Vol. 300 ·No. 5620 ·2003-05-02 ·Pages 808-12

Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, Lalli G, Witherden AS, Hummerich H, Nicholson S, Morgan PJ, Oozageer R, Priestley JV, Averill S, King VR, Ball S, Peters J, Toda T, Yamamoto A, Hiraoka Y, Augustin M, Korthaus D, Wattler S, Wabnitz P, Dickneite C, Lampel S, Boehme F, Peraus G, Popp A, Rudelius M, Schlegel J, Fuchs H, Hrabe de Angelis M, Schiavo G, Shima DT, Russ AP, Stumm G, Martin JE, Fisher EM

Abstract

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.

MeSH Terms

Animals Anterior Horn Cells/pathology Apoptosis Axonal Transport Cell Differentiation Cell Movement Central Nervous System/embryology Chromosome Mapping Dimerization Dyneins/chemistry,genetics,physiology Female Ganglia, Spinal/pathology Golgi Apparatus/metabolism,ultrastructure Heterozygote Homozygote Lewy Bodies/pathology Male Mice Mice, Inbred C3H Mice, Inbred C57BL Motor Neuron Disease/genetics,pathology,physiopathology Motor Neurons/physiology,ultrastructure Mutation Mutation, Missense Nerve Degeneration Peptide Fragments/metabolism Phenotype Point Mutation Spinal Nerves/growth & development Tetanus Toxin/metabolism

Chemicals

Peptide Fragments Tetanus Toxin Dyneins

Authors & Affiliations

39 authors, click to expand affiliations / ORCID

Hafezparast Majid

Department of Neurodegenerative Disease, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.

Klocke Rainer

Ruhrberg Christiana

Marquardt Andreas

Ahmad-Annuar Azlina

Bowen Samantha

Lalli Giovanna

Witherden Abi S

Hummerich Holger

Nicholson Sharon

Morgan P Jeffrey

Oozageer Ravi

Priestley John V

Averill Sharon

King Von R

Ball Simon

Peters Jo

Toda Takashi

Yamamoto Ayumu

Hiraoka Yasushi

Augustin Martin

Korthaus Dirk

Wattler Sigrid

Wabnitz Philipp

Dickneite Carmen

Lampel Stefan

Boehme Florian

Peraus Gisela

Popp Andreas

Rudelius Martina

Schlegel Juergen

Fuchs Helmut

Hrabe de Angelis Martin

Schiavo Giampietro

Shima David T

Russ Andreas P

Stumm Gabriele

Martin Joanne E

Fisher Elizabeth M C

Article Info

Journal

Science (New York, N.Y.)

Abbr.

Science

ISSN

1095-9203

DOI

10.1126/science.1083129

Published

2003-05-02

Pages

808-12

Language

English

Region

United States

NLM ID

0404511

Subset

External Links

PubMed source DOI: 10.1126/science.1083129 View journal details

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Mutations in dynein link motor neuron degeneration to defects in retrograde transport.

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