Human Molecular Genetics Advance Access published online on July 14, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh214
© 2004 by Oxford University Press
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1 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Louis Pasteur Ave., Room 630, Boston, MA 02115; Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263
* To whom correspondence should be addressed. E-mail: mel_feany{at}hms.harvard.edu.
Most human neurodegenerative diseases have a number of features in common including adult onset, progressive degeneration of selected neuronal populations, and the formation of abnormal protein aggregates. Although these shared characteristics raise the possibility of conserved pathogenic mechanisms, the diverse clinical and pathologic features of each disorder indicate significant differences as well. Since a number of human neurodegenerative diseases have now been modeled in Drosophila, and genetic modifiers identified, we have been able to perform a genetic comparison of pathways controlling toxicity in these models. By directly comparing modifiers isolated in models of polyglutamine diseases and in a Drosophila model of tauopathy we find a final common pathway of cell death involving apoptosis. Among the polyglutamine diseases, protein folding and histone acetylation are key common mediators. In addition, two novel modifiers suggest shared pathways of toxicity among all the disorders. Since cell type specificity is a highly salient feature of all neurodegenerative diseases, but most work to date in Drosophila models has been performed in the retina, we determined if similar pathways of toxicity operate in neurons of the Drosophila brain. Many, but not all, retinal modifiers also modify toxicity in postmitotic neurons in the brain. Analysis of polyglutamine toxicity in the adult brain facilitated identification of nicotinamide (Vitamin B3), a vitamin with histone deacetylase inhibiting activity, as a potent suppressor of polyglutamine toxicity. These findings outline common pathways of neurotoxicity, demonstrate of disease- and cell-type specific pathways, and identify a common vitamin as a potential therapy in polyglutamine disorders.
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Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases
2 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Louis Pasteur Ave., Room 630, Boston, MA 02115
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