Abstract
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.
Highlights
Frontotemporal dementia (FTD)3 is a clinical syndrome characterized by progressive deterioration of decision-making abilities, control of behavior, and language, with relative early sparing of memory
We tested whether the effects we observed in the luciferase reporter assay with different histone deacetylase (HDAC) inhibitors would correlate with increased progranulin levels
Familial forms of the disease with known pathogenic mutations provide an opportunity for fast-track development of new therapeutics for FTD
Summary
Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive deterioration of decision-making abilities, control of behavior, and language, with relative early sparing of memory It is the second most frequent presenile dementia disorder, and ϳ25% of the cases are hereditary [1]. The protein encoded by this gene, progranulin ( called GRN protein, human granulin precursor, proepithelin, acrogranin, and PC cell-derived growth factor), is a secreted glycoprotein with growth factorlike and immunomodulatory activities [5] It was recently identified as a TNF receptor antagonist [6]. Increasing progranulin expression from the wild-type allele may prevent or slow down disease progression Following this rationale, Capell et al [11] recently reported that alkalizing drugs and vacuolar ATPase inhibitors increase progranulin expression through a post-transcriptional mechanism. Our objective in this study was to find small molecule enhancers of progranulin transcription by high-throughput screening (HTS) of chemical libraries
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