Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia
Sephton, Chantelle F.
Dewey, Colleen M.
Coughlin, Sarah E.
Lee, Suzee E.
Dries, Daniel R.
Geschwind, Daniel H.
Miller, Bruce L.
Farese, Robert V. Jr.
Posner, Bruce A.
UMass Chan AffiliationsDepartment of Neurology
Document TypeJournal Article
KeywordsDose-Response Relationship, Drug
Histone Deacetylase Inhibitors
Intercellular Signaling Peptides and Proteins
Neuroscience and Neurobiology
MetadataShow full item record
AbstractProgranulin (GRN) haploinsufficiency is a frequent cause of familial frontotemporal dementia, a currently untreatable progressive neurodegenerative disease. By chemical library screening, we identified suberoylanilide hydroxamic acid (SAHA), a Food and Drug Administration-approved histone deacetylase inhibitor, as an enhancer of GRN expression. SAHA dose-dependently increased GRN mRNA and protein levels in cultured cells and restored near-normal GRN expression in haploinsufficient cells from human subjects. Although elevation of secreted progranulin levels through a post-transcriptional mechanism has recently been reported, this is, to the best of our knowledge, the first report of a small molecule enhancer of progranulin transcription. SAHA has demonstrated therapeutic potential in other neurodegenerative diseases and thus holds promise as a first generation drug for the prevention and treatment of frontotemporal dementia.
SourceJ Biol Chem. 2011 May 6;286(18):16101-8. Epub 2011 Mar 23. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/37741
Related ResourcesLink to Article in PubMed