Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease

Huntington’s disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DISC1 led to dysregulation of DISC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DISC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DISC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general

Childhood physical abuse in outpatients with psychosomatic symptoms

Abstract Background In Japan and Asia, few studies have been done of physical and sexual abuse. This study was aimed to determine whether a history of childhood physical abuse is associated with anxiety, depression and self-injurious behavior in outpatients with psychosomatic symptoms. Methods We divided 564 consecutive new outpatients at the Department of Psychosomatic Medicine of Kyushu University Hospital into two groups: a physically abused group and a non-abused group. Psychological test scores and the prevalence of self-injurious behavior were compared between the two groups. Results A history of childhood physical abuse was reported by patients with depressive disorders(12.7%), anxiety disorders(16.7%), eating disorders (16.3%), pain disorders (10.8%), irritable bowel syndrome (12.5%), and functional dyspepsia(7.5%). In both the patients with depressive disorders and those with anxiety disorders, STAI-I (state anxiety) and STAI-II (trait anxiety) were higher in the abused group than in the non-abused group (p In the patients with depressive disorders, the abused group was younger than the non-abused group (p Conclusion A history of childhood physical abuse is associated with psychological distress such as anxiety, depression and self-injurious behavior in outpatients with psychosomatic symptoms. It is important for physicians to consider the history of abuse in the primary care of these patients.</p

The effect of adrenomedullin and cold stress on interleukin-6 levels in some rat tissues

Stress known to stimulate sympathetic activity, as well as the hypothalamic–pituitary–adrenal axis (HPA), produces a significant increase in adrenomedullin (AdM) levels, suggesting a regulatory or protective role for AdM in countering HPA activation that follows a variety of stressors. Stressors can modulate the secretion of proinflammatory cytokines. Interleukin (IL)-6 is a potent activator of the HPA and appears to play a pathogenic role in conditions related to stress. In the present study, we investigated the administration of AdM on IL-6 levels in cold exposed rats. Male Wistar rats were divided into four groups as control, adrenomedullin treatment, cold stress and cold stress+adrenomedullin-treated groups. In the adrenomedullin-treated group, animals received intraperitoneal (i.p.) injection of adrenomedullin (2000 ng/kg body weight) once a day for a week. For the cold stress exposure the rats were kept in separate cages at 10°C for a week. Control group rats were kept in laboratory conditions. The concentration of IL-6 was determined using an enzyme-linked immunosorbent assay (ELISA) kit. When compared to control, IL-6 levels increased significantly in the cold stress- and adrenomedullin-treated groups (P < 0·05). Administration of AdM in addition to cold stress decreased IL-6 levels in lung and liver, but increased in brain and heart when compared to control (P < 0·05). The results suggest that cold stress may induce increase of rat proinflammatory cytokine IL-6 and adrenomedullin may play a regulatory or protective role for cold stress