Thu, 21 Aug 2008 01:22:02 BST CiteULike: giovanni's Herman http://www.citeulike.org/user/giovanni/author/Herman CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/giovanni/article/2801973 <i>Proceedings of the National Academy of Sciences (14 May 2008), 0802545105.</i><br /><br />Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous A peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human -site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human A aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis. 10.1073/pnas.0802545105 Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation Alim Muhammad Ingrid Flores Hong Zhang Rui Yu Agnieszka Staniszewski Emmanuel Planel Mathieu Herman Lingling Ho Robert Kreber Lawrence Honig Barry Ganetzky Karen Duff Ottavio Arancio Scott Small doi:10.1073/pnas.0802545105 Proceedings of the National Academy of Sciences (14 May 2008), 0802545105. 2008-05-15T15:14:02-00:00 2008 Proceedings of the National Academy of Sciences 0802545105 retromer http://www.citeulike.org/user/giovanni/article/875668 <i>Nat Chem Biol, Vol. 2, No. 10. (October 2006), pp. 551-558.</i><br /><br />Expansion of GAA.TTC triplets within an intron in FXN (the gene encoding frataxin) leads to transcription silencing, forming the molecular basis for the neurodegenerative disease Friedreich's ataxia. Gene silencing at expanded FXN alleles is accompanied by hypoacetylation of histones H3 and H4 and trimethylation of histone H3 at Lys9, observations that are consistent with a heterochromatin-mediated repression mechanism. We describe the synthesis and characterization of a class of histone deacetylase (HDAC) inhibitors that reverse FXN silencing in primary lymphocytes from individuals with Friedreich's ataxia. We show that these molecules directly affect the histones associated with FXN, increasing acetylation at particular lysine residues on histones H3 and H4 (H3K14, H4K5 and H4K12). This class of HDAC inhibitors may yield therapeutics for Friedreich's ataxia. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. D Herman K Jenssen R Burnett E Soragni SL Perlman JM Gottesfeld doi:10.1038/nchembio815 Nat Chem Biol, Vol. 2, No. 10. (October 2006), pp. 551-558. 2006-09-27T13:38:00-00:00 2006 Nat Chem Biol 1552-4450 2 10 551 558 frda