Creatine-supplemented diet extends purkinje cell survival in spinocerebellar ataxia type 1 transgenic mice but does not prevent the ataxic phenotype

It is not known why expression of a protein with an expanded polyglutamine region is pathogenic in spinocerebellar ataxia, Huntington's disease and se veral other neurodegenerative diseases. Dietary supplementation with creati ne improves survival and motor performance and delays neuronal atrophy in t he R6/2 transgenic mouse model of Huntington's disease. These effects may b e due to improved energy and calcium homeostasis, enhanced presynaptic glut amate uptake, or protection of mitochondria from the mitochondrial permeabi lity transition. We tested the effects of a 2% creatine-supplemented diet a nd treatment with taurine-conjugated ursodeoxycholic acid, a bile constitue nt that can inhibit the mitochondrial permeability transition, on ataxia an d Purkinje cell survival in a transgenic model of spinocerebellar ataxia ty pe I. After 24 weeks, transgenic mice on the 2% creatine diet had cerebella r phosphocreatine levels that were 72.5% of wildtype controls, compared to 26.8% in transgenic mice fed a control diet. The creatine diet resulted in maintenance of Purkinje cell numbers in these transgenic mice at levels com parable to wildtype controls, while transgenic mice fed a control diet lost over 25% of their Purkinje cell population. Nevertheless, the ataxic pheno type was neither improved nor delayed. Repeated s.c. ursodeoxycholic acid i njections markedly elevated ursodeoxycholic acid levels in the brain withou t adverse effects, but provided no improvement in phenotype or cell surviva l in spinocerebellar ataxia type 1 mice. These results demonstrate that preserving neurons from degeneration is insu fficient to prevent a behavioral phenotype in this transgenic model of poly glutamine disease. In addition, we suggest that the means by which creatine mitigates against the neurodegenerative effects of an ataxin-1 protein con taining an expanded polyglutamine region is through mechanisms other than s tabilization of mitochondrial membranes. (C) 2001 IBRO. Published by Elsevi er Science Ltd. All rights reserved.