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Human Molecular Genetics Advance Access published online on February 4, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn035
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

INSULIN RECEPTOR AND LIPID METABOLISM PATHOLOGY IN ATAXIN-2 KNOCK-OUT MICE

Isabel Lastres-Becker1, Susanne Brodesser2, Dieter Lütjohann3, Mekhman Azizov1, Jana Buchmann4, Edith Hintermann5, Konrad Sandhoff2, Annette Schürmann4, Joachim Nowock1 and Georg Auburger1,*

1 Section of Molecular Neurogenetics, Dept. of Neurology, Building 89, 3rd floor, J.W. Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany 2 LIMES, Program Unit Membrane Biology & Lipid Biochemistry, University of Bonn, c/o Kekulé-Institute of Organic Chemistry and Biochemistry, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany 3 Department of Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany 4 Department of Pharmacology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany. 5 Pharmazentrum Frankfurt, Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES), Johann Wolfgang Goethe University, Frankfurt am Main, Germany.

* Corresponding author: Georg Auburger; E-mail: auburger{at}em.uni-frankfurt.de Section of Molecular Neurogenetics, Dept. of Neurology, Building 26, 5th floor, J.W. Goethe-Universität Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany

Received December 13, 2007; Revised January 30, 2008; Accepted January 30, 2008

Ataxin-2 is a cytoplasmic protein, product of the SCA2 gene. Expansion of the normal polyglutamine tract in the protein leads to the neurodegenerative disorder Spino-Cerebellar Ataxia type 2 (SCA2). Although ataxin-2 has been related to polyribosomes, endocytosis and actin-cytoskeleton organisation, its biological function remains unknown. In the present study, an ataxin-2 deficient mouse (Sca2-/-) was generated to investigate the functional role of this protein. Homozygous mice exhibited reduced fertility and locomotor hyperactivity. In analyses up to the age of 6 months, the absence of ataxin-2 led to abdominal obesity and hepatosteatosis. This was associated with reduced insulin receptor expression in liver and cerebellum, although the mRNA levels were increased indicating a post-transcriptional effect of ataxin-2 on the insulin receptor status. As in insulin resistance syndromes, insulin levels were increased in pancreas and blood serum. In the cerebellum, increased levels of gangliosides and sulfatides, as well as decreased cholesterol dynamics, may be relevant for cellular membrane functions, and alterations in the sphingomyelin cycle may affect second messengers. Thus, the data suggest altered signalling in ataxin-2 deficient organisms.


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