Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice.
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.
Lastres-Becker
Isabel
I
Department of Neurology, J.W. Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
Brodesser
Susanne
S
Lütjohann
Dieter
D
Azizov
Mekhman
M
Buchmann
Jana
J
Hintermann
Edith
E
Sandhoff
Konrad
K
Schürmann
Annette
A
Nowock
Joachim
J
Auburger
Georg
G
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
D000067528:Ataxins; D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D009419:Nerve Tissue Proteins; D013109:Sphingomyelins; D020799:Pancrelipase; D002784:Cholesterol; D011972:Receptor, Insulin