Caveolin-1 regulation of disrupted-in-schizophrenia-1 as a potential therapeutic target for schizophrenia.

Schizophrenia is a debilitating psychiatric disorder manifested in early adulthood. Disrupted-in-schizophrenia-1 (DISC1) is a susceptible gene for schizophrenia (Hodgkinson et al. 2004; Millar et al. 2000; St Clair et al. 1990) implicated in neuronal development, brain maturation, and neuroplasticity (Brandon and Sawa 2011; Chubb et al. 2008). Therefore, DISC1 is a promising candidate gene for schizophrenia, but the molecular mechanisms underlying its role in the pathogenesis of the disease are still poorly understood. Interestingly, caveolin-1 (Cav-1), a cholesterol binding and scaffolding protein, regulates neuronal signal transduction and promotes neuroplasticity. In this study we examined the role of Cav-1 in mediating DISC1 expression in neurons in vitro and the hippocampus in vivo. Overexpressing Cav-1 specifically in neurons using a neuron-specific synapsin promoter (SynCav1) increased expression of DISC1 and proteins involved in synaptic plasticity (PSD95, synaptobrevin, synaptophysin, neurexin, and syntaxin 1). Similarly, SynCav1-transfected differentiated human neurons derived from induced pluripotent stem cells (hiPSCs) exhibited increased expression of DISC1 and markers of synaptic plasticity. Conversely, hippocampi from Cav-1 knockout (KO) exhibited decreased expression of DISC1 and proteins involved in synaptic plasticity. Finally, SynCav1 delivery to the hippocampus of Cav-1 KO mice and Cav-1 KO neurons in culture restored expression of DISC1 and markers of synaptic plasticity. Furthermore, we found that Cav-1 coimmunoprecipitated with DISC1 in brain tissue. These findings suggest an important role by which neuron-targeted Cav-1 regulates DISC1 neurobiology with implications for synaptic plasticity. Therefore, SynCav1 might be a potential therapeutic target for restoring neuronal function in schizophrenia. NEW & NOTEWORTHY: The present study is the first to demonstrate that caveolin-1 can regulate DISC1 expression in neuronal models. Furthermore, the findings are consistent across three separate neuronal models that include rodent neurons (in vitro and in vivo) and human differentiated neurons derived from induced pluripotent stem cells. These findings justify further investigation regarding the modulatory role by caveolin on synaptic function and as a potential therapeutic target for the treatment of schizophrenia.

Alpha cells, the main source of IL-1ß in human pancreas.

Interleukin-1ß (IL-1ß) is known to trigger beta cell dysfunction in vitro and could potentially play a role during the pathogenesis of type 1 diabetes and type 2 diabetes. However, several clinical trials attempting to block IL-1ß function have had minimal success. We therefore re-investigated local expression of IL-1ß in human diabetic and non-diabetic pancreata. We obtained pancreatic tissue sections from the Network for Pancreatic Organ Donors with Diabetes (nPOD) including non-diabetic (n = 9), non-diabetic auto-antibody positive (AAb+, n = 5), type 1 diabetes (n = 6), and type 2 diabetes (n = 6) donors. Islets were systematically investigated for the presence of IL-1ß mRNA by in situ hybridization and IL-1ß protein by indirect immunofluorescence. We found that intra-islet IL-1ß was produced at comparable level in both non-diabetic and diabetic donors. Interestingly, the main source for IL-1ß was alpha cells but not beta cells. Our findings call into question the role of IL-1ß in the diabetic pancreas as it has been proposed in previous literature. Additionally, our results regarding the localization of IL-1ß should lead to further investigation into the role of IL-1ß in the physiology of pancreatic alpha cells.

Increase in Pancreatic Proinsulin and Preservation of ß-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset.

Type 1 diabetes is characterized by the loss of insulin production caused by ß-cell dysfunction and/or destruction. The hypothesis that ß-cell loss occurs early during the prediabetic phase has recently been challenged. Here we show, for the first time in situ, that in pancreas sections from autoantibody-positive (Ab+) donors, insulin area and ß-cell mass are maintained before disease onset and that production of proinsulin increases. This suggests that ß-cell destruction occurs more precipitously than previously assumed. Indeed, the pancreatic proinsulin-to-insulin area ratio was also increased in these donors with prediabetes. Using high-resolution confocal microscopy, we found a high accumulation of vesicles containing proinsulin in ß-cells from Ab+ donors, suggesting a defect in proinsulin conversion or an accumulation of immature vesicles caused by an increase in insulin demand and/or a dysfunction in vesicular trafficking. In addition, islets from Ab+ donors were larger and contained a higher number of ß-cells per islet. Our data indicate that ß-cell mass (and function) is maintained until shortly before diagnosis and declines rapidly at the time of clinical onset of disease. This suggests that secondary prevention before onset, when ß-cell mass is still intact, could be a successful therapeutic strategy.