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Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice
Isabel Lastres-Becker1, Susanne Brodesser, Dieter Lütjohann
1Department of Neurology, J.W. Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
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.
Insights
The absence of ataxin-2 protein in mice leads to obesity, insulin resistance, and altered brain signaling. This study reveals new functions for ataxin-2 in metabolic and neurological health.
Area of Science:
- Neurobiology
- Molecular Biology
- Metabolic Research
Background:
- Ataxin-2 is a protein encoded by the SCA2 gene, linked to Spino-Cerebellar Ataxia type 2.
- Its precise biological functions beyond associations with polyribosomes and endocytosis are largely unknown.
- Understanding ataxin-2's role is crucial for neurodegenerative disease research.
Purpose of the Study:
- To investigate the functional role of ataxin-2 using a knockout mouse model (Sca2(-/-)).
- To identify physiological and molecular consequences of ataxin-2 deficiency.
Main Methods:
- Generation and analysis of ataxin-2 deficient (Sca2(-/-)) mice.
- Phenotypic characterization including fertility, behavior, and metabolic parameters.
- Molecular analyses of insulin receptor expression, lipid profiles, and signaling pathways in liver and cerebellum.
Main Results:
- Sca2(-/-) mice displayed reduced fertility and hyperactivity.
- Deficiency led to abdominal obesity, hepatosteatosis, and insulin resistance by 6 months.
- Post-transcriptional downregulation of insulin receptor in liver and cerebellum was observed.
- Altered ganglioside, sulfatide, and cholesterol dynamics were noted in the cerebellum.
Conclusions:
- Ataxin-2 plays a significant role in regulating metabolic homeostasis and insulin signaling.
- The protein influences cerebellar lipid metabolism and membrane function.
- These findings suggest ataxin-2 deficiency impacts cellular signaling pathways relevant to metabolic and neurological disorders.
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