title: Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice.
abstract: 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 organization, 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 signaling in ataxin-2 deficient organisms.
authors.affiliation: Department of Neurology, J.W. Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lastres-Becker
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Mekhman
authors.initials: M
authors.lastname: Azizov
authors.forename: Jana
authors.initials: J
authors.lastname: Buchmann
authors.forename: Edith
authors.initials: E
authors.lastname: Hintermann
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Nowock
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
mesh_terms: D000818:Animals; D000067528:Ataxins; D001786:Blood Glucose; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D005260:Female; D005298:Fertility; D017353:Gene Deletion; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D009765:Obesity / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D020799:Pancrelipase / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D000067528:Ataxins; D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D009419:Nerve Tissue Proteins; D013109:Sphingomyelins; D020799:Pancrelipase; D002784:Cholesterol; D011972:Receptor, Insulin