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1: Hum Mol Genet. 2004 Sep 15;13(18):2011-8. Epub 2004 Jul 14.
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Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases.

Ghosh S, Feany MB.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 77 Louis Pasteur Avenue, Room 630, Boston, MA 02115, USA.

Most human neurodegenerative diseases have a number of common features, including adult onset, progressive degeneration of selected neuronal populations and formation of abnormal protein aggregates. Although these shared characteristics raise the possibility of conserved pathogenic mechanisms, the diverse clinical and pathological features of each disorder indicate significant differences. As 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 the 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 common key mediators. In addition, two novel modifiers suggest shared pathways of toxicity among all the disorders. Cell-type specificity is a salient feature of all neurodegenerative diseases; however, most work to date in the Drosophila models have been performed in the retina. Therefore, we determined whether 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 the 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 disease- and cell-type specific pathways and identify a common vitamin as a potential therapy in polyglutamine disorders.

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PMID: 15254017 [PubMed - indexed for MEDLINE]