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

W. F. Kaemmerer, C. M P Rodrigues, C. J. Steer, W. C. Low

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


It is not known why expression of a protein with an expanded polyglutamine region is pathogenic in spinocerebellar ataxia, Huntington's disease and several other neurodegenerative diseases. Dietary supplementation with creatine improves survival and motor performance and delays neuronal atrophy in the R6/2 transgenic mouse model of Huntington's disease. These effects may be due to improved energy and calcium homeostasis, enhanced presynaptic glutamate uptake, or protection of mitochondria from the mitochondrial permeability transition. We tested the effects of a 2% creatine-supplemented diet and treatment with taurine-conjugated ursodeoxycholic acid, a bile constituent that can inhibit the mitochondrial permeability transition, on ataxia and Purkinje cell survival in a transgenic model of spinocerebellar ataxia type 1. After 24 weeks, transgenic mice on the 2% creatine diet had cerebellar 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 comparable to wildtype controls, while transgenic mice fed a control diet lost over 25% of their Purkinje cell population. Nevertheless, the ataxic phenotype was neither improved nor delayed. Repeated s.c. ursodeoxycholic acid injections markedly elevated ursodeoxycholic acid levels in the brain without adverse effects, but provided no improvement in phenotype or cell survival in spinocerebellar ataxia type 1 mice. These results demonstrate that preserving neurons from degeneration is insufficient to prevent a behavioral phenotype in this transgenic model of polyglutamine disease. In addition, we suggest that the means by which creatine mitigates against the neurodegenerative effects of an ataxin-1 protein containing an expanded polyglutamine region is through mechanisms other than stabilization of mitochondrial membranes.

Original languageEnglish (US)
Pages (from-to)713-724
Number of pages12
Issue number3
StatePublished - Mar 21 2001

Bibliographical note

Funding Information:
The authors wish to thank Dr Harry T. Orr for providing the transgenic mice for this study, Dr Betsy T. Kren for her valuable technical advice concerning the measurement of creatine in brain homogenates, and Brian Idlekope for his labors in conducting some of the subcutaneous injections of the mice. This investigation was supported in part by the National Institute of Mental Health under National Research Service Award 5 F31 MH11640 to WFK.


  • Huntington's disease
  • Mitochondrial permeability transition
  • Phosphocreatine
  • Polyglutamine diseases
  • Trinucleotide repeat
  • Ursodeoxycholic acid


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