Endocannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 cannabinoid receptors. These receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 cannabinoid receptors has been documented in the basal ganglia of patients with Huntington's disease and animal models. However, the pathophysiological impact of this loss of receptors in Huntington's disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the cannabinoid Δ(9)-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the receptors involves the control of the type 1 cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington's disease. Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington's disease, and suggest that activation of these receptors in patients with Huntington's disease may attenuate disease progression.

Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.

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Morphine and the endogenous opioid peptide ␤-endorphin exert neuromodulatory as well as immunomodulatory effects, which are transduced by -opioid receptors. In this report we show that stimulation with interleukin-4 induces -opioid receptor transcripts in human primary blood cells (T cells and polymorphonuclear leukocytes), immune cell lines (Raji, U-937, and HMEC-1), and dendritic cells. In nonstimulated immune cells this gene is silent. In addition, receptor transcription is up-regulated by interleukin-4 in cultures of primary rat neurons. Transient transfection experiments in Raji and SH SY5Y neuronal cells with human and rat reporter gene constructs linked the interleukin-4 effect directly to cis-active receptor promoter elements located at nucleotide ؊997 on the human gene and nucleotide ؊727 on the rat gene. The interleukin-4 response elements function orientation independently. They bind STAT6 transcription factors as shown by electrophoretic mobility shift assays. In the human gene, a single nucleotide polymorphism within the interleukin-4 response element reduces the trans-activating potential of this element by 50%, which may affect the phenotype of persons carrying this variation. These findings provide a molecular basis for understanding bidirectional interactions between the opioid system and the immune system.Opioids are classically associated with phenomena such as analgesia, respiratory depression, and addiction. The effects of opioids are mediated by at least three different opioid receptors, termed , ␦, and , which belong to the G-protein-coupled membrane receptor family (1, 2). During the last years, evidence has accumulated showing that exogenous opiates like morphine and endogenous opioid peptides derived from the precursors proopiomelanocortin, proenkephalin, and prodynorphin have multiple immunomodulatory properties in addition to their classical functions as neuromodulators. It was stated that the endogenous opioid peptides would now be considered members of the cytokine family if they had been first discovered by immunologists (3). Elucidation of a broad bidirectional communication between the opioid system and the immune system strengthens this concept. Thus, morphine, the prototypical exogenous ligand for the receptor, is an immunosuppressive drug and is responsible for increased susceptibility of opioid addicts to infections (4 -8). Studies with -opioid receptor knockout mice emphasized the role of this receptor in immunosuppression (9). After chronic morphine treatment, these mice developed none of the symptoms characteristic of wild type mice, namely lymphoid organ atrophy, diminished CD4 ϩ / CD8 ϩ cell ratio and strongly reduced natural killer cell activity. In contrast, cytokines modulate the expression of opioid peptide genes and opioid receptor genes. For example, studies with IL-6 1 knockout mice revealed decreased levels of receptors in the brain compared with wild type animals, suggesting a positive regulation of this receptor by IL-6 in vivo (10). In vitro, up-regulation of ...

Opioids and their receptors are key players in a cross-talk between the nervous and immune systems. For example, the endogenous opioid system is activated during inflammation as a physiological feedback mechanism to attenuate inflammatory pain. Herein, we report that in primary human T lymphocytes, Raji B cells, U937 monocytes, primary human polymorphonuclear leukocytes, and mature dendritic cells, the proinflammatory cytokine tumor necrosis factor induced -opioid receptor gene transcription. Transcriptional induction of the gene in immune cells was mediated via tumor necrosis factor receptor type 2. Using selective in vivo disruption of possibly involved transcription factors with decoy oligonucleotides, nuclear factor-B was identified as the factor responsible for induction of the gene in immune cells, whereas activator protein-1 was found to be uninvolved. Nuclear factor-B also mediates upregulation of -opioid receptors in neuronal cells stimulated with tumor necrosis factor. Among six putative nuclear factor-B binding sites on the -opioid receptor gene promoter, three cis-active elements at nt Ϫ2174, Ϫ557, and Ϫ207 were identified using transfection experiments of reporter gene constructs, electrophoretic mobility shift assays, and in vivo binding studies with decoy oligonucleotides. An allelic variation within the Ϫ557 element significantly reduced its trans-activating potency, which may affect regulation of the -opioid receptor gene in persons carrying this mutation. This study suggests a regulatory function of tumor necrosis factor in opioid-mediated processes in neuronal and immune cells, with possible impact on the complex of inflammation-induced analgesia.