SORLA-mediated trafficking of TrkB enhances the response of neurons to BDNF

Stimulation of neurons with brain-derived neurotrophic factor (BDNF) results in robust induction of SORLA, an intracellular sorting receptor of the VPS10P domain receptor gene family. However, the relevance of SORLA for BDNF-induced neuronal responses has not previously been investigated. We now demonstrate that SORLA is a sorting factor for the tropomyosin-related kinase receptor B (TrkB) that facilitates trafficking of this BDNF receptor between synaptic plasma membranes, post-synaptic densities, and cell soma, a step critical for neuronal signal transduction. Loss of SORLA expression results in impaired neuritic transport of TrkB and in blunted response to BDNF in primary neurons; and it aggravates neuromotoric deficits caused by low BDNF activity in a mouse model of Huntington's disease. Thus, our studies revealed a key role for SORLA in mediating BDNF trophic signaling by regulating the intracellular location of TrkB

Home practice in Mindfulness-Based Cognitive Therapy and Mindfulness-Based Stress Reduction:A systematic review and meta-analysis of participants' mindfulness practice and its association with outcomes

Mindfulness-Based Cognitive Therapy (MBCT) and Mindfulness-Based Stress Reduction (MBSR) emphasize the importance of mindfulness practice at home as an integral part of the program. However, the extent to which participants complete their assigned practice is not yet clear, nor is it clear whether this practice is associated with positive outcomes. For this systematic review and meta-analysis, searches were performed using Scopus and PubMed for studies published through to the end of 2015, reporting on formal home practice of mindfulness by MBSR or MBCT participants. Across 43 studies (N=1427), the pooled estimate for participants’ home practice was 64% of the assigned amount, equating to about 30 minutes per day, six days per week [95% CI 60 – 69%]. There was substantial heterogeneity associated with this estimate. Across 28 studies (N=898), there was a small but significant association between participants’ self-reported home practice and intervention outcomes (r = 0·26, 95% CI 0·19, – 0·34). MBSR and MBCT participants report completing substantial formal mindfulness practice at home over the eight-week intervention, albeit less than assigned amounts. There is a small but significant association between the extent of formal practice and positive intervention outcomes for a wide range of participants

A systematic review of mechanisms of change in mindfulness-based cognitive therapy in the treatment of recurrent major depressive disorder

AbstractBackgroundThe investigation of treatment mechanisms in randomized controlled trials has considerable clinical and theoretical relevance. Despite the empirical support for the effect of mindfulness-based cognitive therapy (MBCT) in the treatment of recurrent major depressive disorder (MDD), the specific mechanisms by which MBCT leads to therapeutic change remain unclear.ObjectiveBy means of a systematic review we evaluate how the field is progressing in its empirical investigation of mechanisms of change in MBCT for recurrent MDD.MethodTo identify relevant studies, a systematic search was conducted. Studies were coded and ranked for quality.ResultsThe search produced 476 articles, of which 23 were included. In line with the theoretical premise, 12 studies found that alterations in mindfulness, rumination, worry, compassion, or meta-awareness were associated with, predicted or mediated MBCT's effect on treatment outcome. In addition, preliminary studies indicated that alterations in attention, memory specificity, self-discrepancy, emotional reactivity and momentary positive and negative affect might play a role in how MBCT exerts its clinical effects.ConclusionThe results suggest that MBCT could work through some of the MBCT model's theoretically predicted mechanisms. However, there is a need for more rigorous designs that can assess greater levels of causal specificity

Retromer and the cation-independent mannose 6-phosphate receptor-Time for a trial separation?

The retromer cargo-selective complex (CSC) comprising Vps35, Vps29 and Vps26 mediates the endosome-to-Golgi retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR). Or does it? Recently published data have questioned the validity of this long-established theory. Here, the evidence for and against a role for the retromer CSC in CIMPR endosome-to-Golgi retrieval is examined in the light of the new data that the SNX-BAR dimer is actually responsible for CIMPR retrieval

Designing technology tools to support engagement in mindfulness-based interventions: an analysis of teacher and student experiences

Standard mindfulness-based interventions have significant at-home assignments of formal mindfulness practice as a key component. Engagement with formal home practice has been correlated with treatment outcomes, but participants often complete less than the assigned amounts. Here, we explore the requirements for technology tools that can support and encourage home practice, in a way that is appropriate and consistent with the core principles of mindfulness-based interventions. Interviews were held with a group of five highly experienced mindfulness teachers and a group of five participants who had previously completed an eight-week course. Data was subjected to thematic analysis. A key finding was that providing teachers with information on how students practice could support communication around difficulties with home practice. We also identified questions around the appropriateness of adapting the course in response to participant difficulties and participant preferences. Both teachers and students made numerous suggestions for ways to augment their training using technology, such as via practice reminders and provision of teacher-specific content. Finally, a major design issue for technology developers is how to support participants in reflecting on their experiences of mindfulness practice, and subsequent learning, but not to critically evaluate their practice

Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing

sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD

Mindfulness-based interventions in epilepsy: a systematic review

Mindfulness based interventions (MBIs) are increasingly used to help patients cope with physical and mental long-term conditions (LTCs). Epilepsy is associated with a range of mental and physical comorbidities that have a detrimental effect on quality of life (QOL), but it is not clear whether MBIs can help. We systematically reviewed the literature to determine the effectiveness of MBIs in people with epilepsy. Medline, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, Allied and Complimentary Medicine Database, and PsychInfo were searched in March 2016. These databases were searched using a combination of subject headings where available and keywords in the title and abstracts. We also searched the reference lists of related reviews. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Three randomised controlled trials (RCTs) with a total of 231 participants were included. The interventions were tested in the USA (n = 171) and China (Hong Kong) (n = 60). Significant improvements were reported in depression symptoms, quality of life, anxiety, and depression knowledge and skills. Two of the included studies were assessed as being at unclear/high risk of bias - with randomisation and allocation procedures, as well as adverse events and reasons for drop-outs poorly reported. There was no reporting on intervention costs/benefits or how they affected health service utilisation. This systematic review found limited evidence for the effectiveness of MBIs in epilepsy, however preliminary evidence suggests it may lead to some improvement in anxiety, depression and quality of life. Further trials with larger sample sizes, active control groups and longer follow-ups are needed before the evidence for MBIs in epilepsy can be conclusively determined