PgmNr D1376: Analysis of glucose metabolism during pathogenesis of Spinocerebellar Ataxia Type 1.

Authors:
J. R. Diaz 1,2 ; A. Perez 1,2 ; T. Gallego-Flores 1,2 ; Y. Wan 1,2 ; T. Inoue 1 ; A. Chai 1,2 ; C. Karakas 1,2 ; I. Al-Ramahi 1,2 ; M. Maletić-Savatić 1,2 ; M. Gaber 1 ; R. Samaco 1,2 ; Z. Liu 1,2 ; H. Orr 3 ; J. Botas 1,2


Institutes
1) Baylor College of Medicine, Houston, TX; 2) Jan and Dan Duncan NRI, Texas Children Hospital. Houston, TX; 3) University of Minnesota, Institute for Translational Neuroscience, Minnesota.


Keyword: neural disorder

Abstract:

Spinocerebellar ataxia type 1 (SCA1) is one of nine Polyglutamine Diseases caused by CAG expansion in the coding region of the corresponding gene. In SCA1, CAG expanded repeats cause an abnormally long glutamine tract in ATXN1 protein and trigger a gain of function pathogenic mechanism that leads to a progressive neurodegenerative disorder. The brain regions primarily affected are the cerebellum and the brainstem. Previous study reported that insulin sensitivity and insulin secretion are abnormal in SCA1 patients. We hypothesize that expression of mutant ATXN1 impairs glucose metabolism and use multiple approaches to test this hypothesis using mice and Drosophila disease models. Gene expression analyses in SCA1 mice and flies suggest glucose uptake deficiency in neuronal cells. Confirming these results, positron emission tomography imaging suggests lower glucose level in the cerebellum of SCA1 transgenic mice. Metabolomic analyses in SCA1 fly neurons reveal a decrease in glucose metabolism metabolites. We carried out a genetic screen in Drosophila of all genes encoding glycolytic enzymes for potential modifier genes of SCA1 pathogenesis. We found that knocking down glycolytic genes ameliorates neurodegeneration by reducing steady-state levels of mutant ATXN1 protein. Together these data suggest that glucose metabolism impairments contribute to SCA1 pathogenesis and reveal new therapeutic approaches to decrease ATXN1 neurotoxicity.