Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 18, Pages -Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.193433
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Funding
- National Institutes of Health
- Consortium for Frontotemporal Dementia Research
- California Institute for Regenerative Medicine
- National Cell Repository for Alzheimer's Disease
- Ted Nash Long Life Foundation
- Welch Foundation
- Humboldt Foundation
- American Health Assistance Foundation
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Progranulin (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.
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