Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. Here we show that a similar form of functional antagonism is produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of MAGL. Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity, and desensitization of brain CB1 receptors. These data contrasted with blockade of fatty acid amide hydrolase (FAAH), an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.

Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2 300Q transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2 300Q transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment.rologic disorder caused by a CAG repeat expansion within the coding region of the HD gene (Htt), resulting in a mutant protein (htt) with a lengthened polyglutamine tract (1). Mutant htt protein has been shown to disrupt transcription by multiple mechanisms, but it is unclear which are most important to pathology (2-4). By interacting with specific transcription factors, htt can alter the expression of clusters of genes controlled by those factors. For example, several genes driven by Sp1, which has been shown to interact with htt (5, 6), show decreased mRNA expression in human HD and in mouse models of HD (7). Alternatively, htt may have more global effects on transcription by disrupting core transcriptional machinery (8, 9) or by altering posttranslational modifications of histones, resulting in condensed chromatin structure (10-13). Understanding the basis for transcriptional dysregulation is important for choosing appropriate drug-discovery strategies.Manifestations of transcriptional dysregulation are evident from several gene-profiling studies, which have revealed alterations in the expression of large numbers of genes in the brains of different HD mouse models and in human subjects with HD (7, 14-16). Many of the expression changes in mouse models are observed in early stages of illness before the onset of symptoms, suggesting that gene expression alterations may be pathogenic.Because o...

SUMMARY The inherited neurodegenerative disease Friedreich’s ataxia (FRDA) is caused by GAA•TTC triplet repeat hyper-expansions within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAA•TTC repeats causes heterochromatin-mediated gene silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts by transcription factor reprogramming. FXN gene repression is maintained in the iPSCs, as are the global gene expression signatures reflecting the human disease. GAA•TTC repeats uniquely in FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme MSH2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in pluripotent cells, occupies FXN intron 1, and shRNA silencing of MSH2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.

Results from clinical and imaging studies provide evidence for changes in schizophrenia with disease progression, however, the underlying molecular differences that may occur at different stages of illness have not been investigated. To test the hypothesis that the molecular basis for schizophrenia changes from early to chronic illness, we profiled genome-wide expression patterns in prefrontal cortex of schizophrenic subjects at different stages of illness, along with their age-and sex-matched controls. Results show that gene expression profiles change dramatically depending on the stage of illness, whereby the greatest number and magnitude of gene expression differences were detected in subjects with short-term illness (≤ 4 years from diagnosis). Comprehensive pathways analyses revealed that each defined stage of illness was associated with dysfunction in both distinct, as well as overlapping systems. Short-term illness was particularly associated with disruptions in gene transcription, metal ion binding, RNA processing and vesicle-mediated transport. In contrast, longterm illness was associated with inflammation, stimulus-response and immune functions. We validated expression differences of 12 transcripts associated with these various functions by realtime PCR analysis. While only four genes, SAMSN1, CDC42BPB, DSC2 and PTPRE, were consistently expressed across all groups, there was dysfunction in overlapping systems among all stages, including cellular signal transduction, lipid metabolism and protein localization. Our results demonstrate that the molecular basis for schizophrenia changes from early to chronic stages, providing evidence for a changing nature of schizophrenia with disease progression.

The current obesity epidemic is staggering in terms of its magnitude and public health impact. Current guidelines recommend continuous energy restriction (CER) along with a comprehensive lifestyle intervention as the cornerstone of obesity treatment, yet this approach produces modest weight loss on average. Recently, there has been increased interest in identifying alternative dietary weight loss strategies that involve restricting energy intake to certain periods of the day or prolonging the fasting interval between meals (i.e., intermittent energy restriction, IER). These strategies include intermittent fasting (IMF; >60% energy restriction on 2–3 days per week, or on alternate days) and time-restricted feeding (TRF; limiting the daily period of food intake to 8–10 h or less on most days of the week). Here, we summarize the current evidence for IER regimens as treatments for overweight and obesity. Specifically, we review randomized trials of ≥8 weeks in duration performed in adults with overweight or obesity (BMI ≥ 25 kg/m2) in which an IER paradigm (IMF or TRF) was compared to CER, with the primary outcome being weight loss. Overall, the available evidence suggests that IER paradigms produce equivalent weight loss when compared to CER, with 9 out of 11 studies reviewed showing no differences between groups in weight or body fat loss.