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The Journal of Neuroscience, August 11, 2004, 24(32):7118-7127; doi:10.1523/JNEUROSCI.1233-04.2004

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Neurobiology of Disease
Disrupted Spermine Homeostasis: A Novel Mechanism in Polyglutamine-Mediated Aggregation and Cell Death

C. A. Colton,¹ Q. Xu,¹ J. R. Burke,¹ S. Y. Bae,¹ J. K. Wakefield,² A. Nair,² W. J. Strittmatter,¹ and M. P. Vitek¹

¹Deane Laboratory, Division of Neurology, Duke University Medical Center, Durham, North Carolina 27710, and ²Tranzyme Inc., Research Triangle Park, North Carolina 27709

Our data suggest a novel mechanism whereby pathological-length polyglutamine (polyQ) proteins promote the spermine synthetic pathway, increasing polyQ-aggregation and cell death. As detected in a cell-free turbidity assay, spermine promotes aggregation of thio-polyQ62 in a dose-dependent manner. Using a stable neuronal cell line expressing pathological-length [polyQ57-yellow fluorescent protein (YFP) (Q57)] or non-pathological-length [polyQ19-YFP (Q19)] polyglutamine protein, we show that multiple steps in the production of polyamines are affected in Q57 cells, suggesting dysfunctional spermine homeostasis. As the building block for spermine synthesis, arginine transport is significantly increased in neuronal cell lines stably expressing Q57. Q57 lines displayed upregulated basal and inducible arginase I activities that were not seen in polyQ19-YFP lines. Normal induction of spermidine/spermine N-acetyltransferase in Q19 lines regulating back-conversion of spermine, thereby reducing spermine levels, however, was not observed in Q57 lines. Pharmacological activation of ornithine decarboxylase (ODC), a key enzyme of the polyamine synthetic pathway, increased cellular aggregates and increased cell death in Q57 cells not observed in Q19 cells. Inhibition of ODC by difluoromethylornithine prevented basal and induced cell death in Q57 cells, demonstrating a central role for polyamines in this process.

Key words: spermine; polyglutamine; Huntington's disease; difluoromethylornithine; protein aggregation; nitric oxide

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Received April 1, 2004; revised June 25, 2004; accepted June 28, 2004.

This article has been cited by other articles:

				M. A. Ariano, C. Cepeda, C. R. Calvert, J. Flores-Hernandez, E. Hernandez-Echeagaray, G. J. Klapstein, S. H. Chandler, N. Aronin, M. DiFiglia, and M. S. Levine Striatal Potassium Channel Dysfunction in Huntington's Disease Transgenic Mice J Neurophysiol, May 1, 2005; 93(5): 2565 - 2574. [Abstract] [Full Text] [PDF]

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