DcpS is a transcript-specific modulator of RNA in mammalian cells.

The scavenger decapping enzyme DcpS is a multifunctional protein initially identified by its property to hydrolyze the resulting cap structure following 3' end mRNA decay. In Saccharomyces cerevisiae, the DcpS homolog Dcs1 is an obligate cofactor for the 5'-3' exoribonuclease Xrn1 while the Caenorhabditis elegans homolog Dcs-1, facilitates Xrn1 mediated microRNA turnover. In both cases, this function is independent of the decapping activity.

The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models.

Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to the functional loss of the SMN1 gene and the inability of its paralog, SMN2, to fully compensate due to reduced exon 7 splicing efficiency. Since SMA patients have at least one copy of SMN2, drug discovery campaigns have sought to identify SMN2 inducers. C5-substituted quinazolines increase SMN2 promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing.

The DcpS inhibitor RG3039 improves motor function in SMA mice.

Spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 (SMN1) gene, retention of the survival motor neuron 2 (SMN2) gene and insufficient expression of full-length survival motor neuron (SMN) protein. Quinazolines increase SMN2 promoter activity and inhibit the ribonucleic acid scavenger enzyme DcpS. The quinazoline derivative RG3039 has advanced to early phase clinical trials.

Development of frataxin gene expression measures for the evaluation of experimental treatments in Friedreich's ataxia.

Background: Friedreich ataxia is a progressive neurodegenerative disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene and, ultimately, a deficiency in the levels of functional frataxin protein. Heterozygous carriers of the expansion express approximately 50% of normal frataxin levels yet manifest no clinical symptoms, suggesting that therapeutic approaches that increase frataxin may be effective even if frataxin is raised only to carrier levels. Small molecule HDAC inhibitor compounds increase frataxin mRNA and protein levels, and have beneficial effects in animal models of FRDA.

Rationale for the development of 2-aminobenzamide histone deacetylase inhibitors as therapeutics for Friedreich ataxia.

Numerous studies have pointed to histone deacetylase inhibitors as potential therapeutics for various neurodegenerative diseases, and clinical trials with several histone deacetylase inhibitors have been performed or are under way. However, histone deacetylase inhibitors tested to date either are highly cytotoxic or have very low specificities for different histone deacetylase enzymes. The authors' laboratories have identified a novel class of histone deacetylase inhibitors (2-aminobenzamides) that reverses heterochromatin-mediated silencing of the frataxin (FXN) gene in Friedreich ataxia.

Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease.

We have previously demonstrated amelioration of Huntington's disease (HD)-related phenotypes in R6/2 transgenic mice in response to treatment with the novel histone deacetylase (HDAC) inhibitor 4b. Here we have measured the selectivity profiles of 4b and related compounds against class I and class II HDACs and have tested their ability to restore altered expression of genes related to HD pathology in mice and to rescue disease effects in cell culture and Drosophila models of HD. R6/2 transgenic and wild-type (wt) mice received daily injections of HDAC inhibitors for 3 days followed by real-time PCR analysis to detect expression differences for 13 HD-related genes.

A gene expression phenotype in lymphocytes from Friedreich ataxia patients.

Objective: Gene expression studies in peripheral tissues from patients with neurodegenerative disorders can provide insights into disease pathogenesis, and identify potential biomarkers, an important goal of translational research in neurodegeneration. Friedreich Ataxia (FRDA) is a chronic neurodegenerative disease caused by reduced transcription of frataxin, a ubiquitously expressed protein. We studied in vitro lymphocytes from FRDA patients and carriers to identify a peripheral gene expression phenotype.

Evaluation of histone deacetylase inhibitors as therapeutics for neurodegenerative diseases.

Various neurodegenerative diseases are associated with aberrant gene expression. We recently identified a novel class of pimelic o-aminobenzamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease (HD). Here, we describe the various techniques used in our laboratories to dissect mechanisms of gene silencing in FRDA and HD, and to test our HDAC inhibitors for their ability to reverse changes in gene expression in cellular models.

Integrating multiple evidence sources to predict transcription factor binding in the human genome.

Information about the binding preferences of many transcription factors is known and characterized by a sequence binding motif. However, determining regions of the genome in which a transcription factor binds based on its motif is a challenging problem, particularly in species with large genomes, since there are often many sequences containing matches to the motif but are not bound. Several rules based on sequence conservation or location, relative to a transcription start site, have been proposed to help differentiate true binding sites from random ones.

Chemical probes identify a role for histone deacetylase 3 in Friedreich's ataxia gene silencing.

We recently identified a class of pimelic diphenylamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease. Here, we describe chemical approaches to identify the HDAC enzyme target of these inhibitors. Incubation of a trifunctional activity-based probe with a panel of class I and class II recombinant HDAC enzymes, followed by click chemistry addition of a fluorescent dye and gel electrophoresis, identifies HDAC3 as a unique high-affinity target of the probe.