Remodeling the Proteostasis Network to Rescue Glucocerebrosidase Variants by Inhibiting ER-Associated Degradation and Enhancing ER Folding

Gaucher’s disease (GD) is characterized by loss of lysosomal glucocerebrosidase (GC) activity. Mutations in the gene encoding GC destabilize the protein’s native folding leading to ER-associated degradation (ERAD) of the misfolded enzyme. Enhancing the cellular folding capacity by remodeling the proteostasis network promotes native folding and lysosomal activity of mutated GC variants. However, proteostasis modulators reported so far, including ERAD inhibitors, trigger cellular stress and lead to induction of apoptosis. We show herein that lacidipine, an L-type Ca2+ channel blocker that also inhibits ryanodine receptors on the ER membrane, enhances folding, trafficking and lysosomal activity of the most severely destabilized GC variant achieved via ERAD inhibition in fibroblasts derived from patients with GD. Interestingly, reprogramming the proteostasis network by combining modulation of Ca2+ homeostasis and ERAD inhibition remodels the unfolded protein response and dramatically lowers apoptosis induction typically associated with ERAD inhibition

Development of aggression subtypes from childhood to adolescence:a group-based multi-trajectory modelling perspective

The persistence of elevated subtypes of aggression beginning in childhood have been associated with long-term maladaptive outcomes. Yet it remains unclear to what extent there are clusters of individuals following similar developmental trajectories across forms (i.e., physical and indirect) and functions (i.e., proactive and reactive) of aggression. We aimed to identify groups of children with distinct profiles of the joint development of forms and functions of aggression and to identify risk factors for group membership. A sample of 787 children was followed from birth to adolescence. Parent and teacher reports, and standardised assessments were used to measure two forms and two functions of aggressive behaviour, between six and 13 years of age along with preceding child, maternal, and family-level risk-factors. Analyses were conducted using a group-based multi-trajectory modelling approach. Five trajectory groups emerged: non-aggressors, low-stable, moderate-engagers, high-desisting, and high-chronic. Coercive parenting increased membership risk in the moderate-engagers and high-chronic groups. Lower maternal IQ increased membership risk in both high-desisting and high-chronic groups, whereas maternal depression increased membership risk in the high-desisting group only. Never being breastfed increased membership risk in the moderate-engagers group. Boys were at greater risk for belonging to groups displaying elevated aggression. Individuals with chronic aggression problems use all subtypes of aggression. Risk factors suggest that prevention programs should start early in life and target mothers with lower IQ. Strategies to deal with maternal depression and enhance positive parenting while replacing coercive parenting tactics should be highlighted in programming efforts

New Insights in the IP3 Receptor and Its Regulation

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a Ca2+-release channel mainly located in the endoplasmic reticulum (ER). Three IP3R isoforms are responsible for the generation of intracellular Ca2+ signals that may spread across the entire cell or occur locally in so-called microdomains. Because of their ubiquitous expression, these channels are involved in the regulation of a plethora of cellular processes, including cell survival and cell death. To exert their proper function a fine regulation of their activity is of paramount importance. In this review, we will highlight the recent advances in the structural analysis of the IP3R and try to link these data with the newest information concerning IP3R activation and regulation. A special focus of this review will be directed towards the regulation of the IP3R by protein-protein interaction. Especially the protein family formed by calmodulin and related Ca2+-binding proteins and the pro- and anti-apoptotic/autophagic Bcl-2-family members will be highlighted. Finally, recently identified and novel IP3R regulatory proteins will be discussed. A number of these interactions are involved in cancer development, illustrating the potential importance of modulating IP3R-mediated Ca2+ signaling in cancer treatment.status: publishe