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Molecular & Cellular Proteomics 1:366-375, 2002.
© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Alterations in the Mouse and Human Proteome Caused by Huntington’s Disease^*

Claus Zabel, Daniel C. Chamrad, Josef Priller^¶, Ben Woodman^||, Helmut E. Meyer^,**, Gillian P. Bates^|| and Joachim Klose^,

Institut für Humangenetik, Universitätsklinikum Charité, 13353 Berlin, Germany
Protagen AG, 44227 Dortmund, Germany
^¶ Klinik für Neurologie, Universitätsklinikum Charité, 10117 Berlin, Germany
^|| Division of Medical and Molecular Genetics, GKT School of Medicine, Guy’s Hospital, London SE1 9RT, United Kingdom
^** Institut für Physiologische Chemie, Ruhr-Universität Bochum, 44780 Bochum, Germany

Huntington’s disease is an autosomal dominantly inherited disease that usually starts in midlife and inevitably leads to death. In our effort to identify proteins involved in processes upstream or downstream of the disease-causing huntingtin, we studied the proteome of a well established mouse model by large gel two-dimensional electrophoresis. We could demonstrate for the first time at the protein level that 1-antitrypsin and B-crystalline both decrease in expression over the course of disease. Importantly, the 1-antitrypsin decrease in the brain precedes that in liver and testes in mice. Reduced expression of the serine protease inhibitors 1-antitrypsin and contraspin was found in liver, heart, and testes close to terminal disease. Decreased expression of the chaperone B-crystallin was found exclusively in the brain. In three brain regions obtained post-mortem from Huntington’s disease patients, 1-antitrypsin expression was also altered. Reduced expression of the major urinary proteins not found in the brain was seen in the liver of affected mice, demonstrating that the disease exerts its influence outside the brain of transgenic mice at the protein level. Maintaining 1-antitrypsin and B-crystallin availability during the course of Huntington’s disease might prevent neuronal cell death and therefore could be useful in delaying the disease progression.

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