Assembly, trafficking and function of gamma-secretase

gamma-Secretase catalyzes the final cleavage of the beta-amyloid precursor protein to generate amyloid-beta peptide, the principal component of amyloid plaques in the brains of patients suffering from Alzheimer's disease. Here, we review the identification of gamma-secretase as a protease complex and its assembly and trafficking to its site(s) of cellular function. In reconstitution experiments, gamma-secretase was found to be composed of four integral membrane proteins, presenilin (PS), nicastrin (NCT), PEN-2 and APH-1 that are essential and sufficient for gamma-secretase activity. PS, which serves as a catalytic subunit of gamma-secretase, was identified as a prototypic member of novel aspartyl proteases of the GxGD type. In human cells, gamma-secretase could be further defined as a heterogeneous activity consisting of distinct complexes that are composed of PS1 or PS2 and APH-1a or APH-1b homologues together with NCT and PEN-2. Using green fluorescent protein as a reporter we localized PS and gamma-secretase activity at the plasma membrane and endosomes. Investigation of gamma-secretase complex assembly in knockdown and knockout cells of the individual subunits allowed us to develop a model of complex assembly in which NCT and APH-1 first stabilize PS before PEN-2 assembles as the last component. Furthermore, we could map domains in PS and PEN-2 that govern assembly and trafficking of the complex. Finally, Rer1 was identified as a PEN-2-binding protein that serves a role as an auxiliary factor for gamma-secretase complex assembly. Copyright (c) 2006 S. Karger AG, Basel

Analysis of the genetic basis of height in large Jewish nuclear families.

Despite intensive study, most of the specific genetic factors that contribute to variation in human height remain undiscovered. We conducted a family-based linkage study of height in a unique cohort of very large nuclear families from a founder (Jewish) population. This design allowed for increased power to detect linkage, compared to previous family-based studies. Loci we identified in discovery families could explain an estimated lower bound of 6% of the variance in height in validation families. We showed that these loci are not tagging known common variants associated with height. Rather, we suggest that the observed signals arise from variants with large effects that are rare globally but elevated in frequency in the Jewish population

Learning from support workers: can a dramatherapy group offer a community provision to support changes in care for people with learning disabilities and mental health difficulties?

1.1 Background The UK Government's Transforming Care Agenda for people with learning disabilities has struggled to meet its goals of reducing inpatient beds and building community‐based support. This article reports on the experiences of support staff who attended dramatherapy groups developed to assist transitions from an inpatient hospital and to prevent re‐admissions through post‐discharge support. The groups provide ongoing support and a place where relationships can be developed between supporter and those supported. 1.2 Materials and Methods A focus group with a purposive sample of paid support staff. The data was synthesised using a thematic framework approach. 1.3 Results Themes include: (a) new way of supporting and (b) hospital connection. The groups helped improve social interaction, friendship building, communication and self‐confidence. Additional benefits include the pooling of support and a connection with professionals that enables difficulties to be caught early. 1.4 Conclusions Support workers valued these dramatherapy groups, recognising how the intervention enabled people with learning disabilities to develop relationships and provide easy access to mental health professionals. Support staff also found benefits for themselves which included shared support and an increased understanding and insight into the people they support

Cost-effectiveness of population based BRCA testing with varying Ashkenazi Jewish ancestry.

BACKGROUND: Population-based BRCA1/BRCA2 testing has been found to be cost-effective compared with family history-based testing in Ashkenazi-Jewish women were >30 years old with 4 Ashkenazi-Jewish grandparents. However, individuals may have 1, 2, or 3 Ashkenazi-Jewish grandparents, and cost-effectiveness data are lacking at these lower BRCA prevalence estimates. We present an updated cost-effectiveness analysis of population BRCA1/BRCA2 testing for women with 1, 2, and 3 Ashkenazi-Jewish grandparents. STUDY DESIGN: Decision analysis model. METHODS: Lifetime costs and effects of population and family history-based testing were compared with the use of a decision analysis model. 56% BRCA carriers are missed by family history criteria alone. Analyses were conducted for United Kingdom and United States populations. Model parameters were obtained from the Genetic Cancer Prediction through Population Screening trial and published literature. Model parameters and BRCA population prevalence for individuals with 3, 2, or 1 Ashkenazi-Jewish grandparent were adjusted for the relative frequency of BRCA mutations in the Ashkenazi-Jewish and general populations. Incremental cost-effectiveness ratios were calculated for all Ashkenazi-Jewish grandparent scenarios. Costs, along with outcomes, were discounted at 3.5%. The time horizon of the analysis is "life-time," and perspective is "payer." Probabilistic sensitivity analysis evaluated model uncertainty. RESULTS: Population testing for BRCA mutations is cost-saving in Ashkenazi-Jewish women with 2, 3, or 4 grandparents (22-33 days life-gained) in the United Kingdom and 1, 2, 3, or 4 grandparents (12-26 days life-gained) in the United States populations, respectively. It is also extremely cost-effective in women in the United Kingdom with just 1 Ashkenazi-Jewish grandparent with an incremental cost-effectiveness ratio of £863 per quality-adjusted life-years and 15 days life gained. Results show that population-testing remains cost-effective at the £20,000-30000 per quality-adjusted life-years and $100,000 per quality-adjusted life-years willingness-to-pay thresholds for all 4 Ashkenazi-Jewish grandparent scenarios, with ≥95% simulations found to be cost-effective on probabilistic sensitivity analysis. Population-testing remains cost-effective in the absence of reduction in breast cancer risk from oophorectomy and at lower risk-reducing mastectomy (13%) or risk-reducing salpingo-oophorectomy (20%) rates. CONCLUSION: Population testing for BRCA mutations with varying levels of Ashkenazi-Jewish ancestry is cost-effective in the United Kingdom and the United States. These results support population testing in Ashkenazi-Jewish women with 1-4 Ashkenazi-Jewish grandparent ancestry

p53-dependent control of transactivation of the Pen2 promoter by presenilins

The senile plaques found in the brains of patients with Alzheimer's disease are mainly due to the accumulation of amyloid β-peptides (Aβ) that are liberated by γ-secretase, a high molecular weight complex including presenilins, PEN-2, APH-1 and nicastrin. The depletion of each of these proteins disrupts the complex assembly into a functional protease. Here, we describe another level of regulation of this multimeric protease. The depletion of both presenilins drastically reduces Pen2 mRNA levels and its promoter transactivation. Furthermore, overexpression of presenilin-1 lowers Pen2 promoter transactivation, a phenotype abolished by a double mutation known to prevent presenilin-dependent γ-secretase activity. PEN-2 expression is decreased by depletion of β-amyloid precursor protein (APP) and increased by the APP intracellular domain (AICD). We show that AICD and APP complement for Pen2 mRNA levels in APP/APLP1-2 knockout fibroblasts. Interestingly, overexpression of presenilin-2 greatly increases Pen2 promoter transactivation. The opposite effect triggered by both presenilins was reminiscent of our previous study, which showed that these two proteins elicit antagonistic effects on p53. Therefore, we examined the contribution of p53 on Pen2 transcription. Pen2 promoter transactivation, and Pen2 mRNA and protein levels were drastically reduced in p53–/– fibroblasts. Furthermore, PEN-2 expression could be rescued by p53 complementation in p53- and APP-deficient cells. Interestingly, PEN-2 expression was also reduced in p53-deficient mouse brain. Overall, our study describes a p53-dependent regulation of PEN-2 expression by other members of the γ-secretase complex, namely presenilins

Rattling Europe’s ordoliberal ‘iron cage’ : the contestation of austerity in Southern Europe

This article explains the popular revolt against austerity in Southern Europe as the outcome of profound politico-economic changes that are shaped by the transformation of the European Union’s (EU’s) macro-economic governance. It comprises three parts. The first part demonstrates how ordoliberalism – the Germanic variant of (neo)liberal economic thinking – was embedded in the EU’s new macro-economic governance, in processes that constitutionalise austerity and remove democratic controls over the economy. The second part examines the impact of austerity-driven reforms on welfare and employment in the aftermath of the sovereign debt crisis. These reforms undermined the social reproduction of Southern Europe’s familistic welfare model by destabilising three key pillars of social protection: employment security for households’ primary earners; small property ownership; and pension adequacy. The third part analyses the emergence of anti-austerity social politics in Southern Europe, both parliamentary and grassroots, and assesses their effectiveness in light of the collapse of public trust in both EU and domestic political institutions. The article concludes with our reflections on the fragility of EU’s integration process under the hegemony of ordoliberalism

The shifting terrain of sex and power: From the 'sexualisation of culture' to Me Too

In this short article we will aim to do three things. First, we want to use this opportunity to reflect on some of the changes we have seen in the scholarly field of gender, sexuality, and intimacy over this period, and on new emerging directions. Second, we want to discuss the move away from discussions of ‘sexualization’ to a more critical and political register interested in a variety of ways in which sex and power intersect. Thirdly, we will discuss MeToo as an example of this shifted form of engagement, and raise some questions about its possibilities and limitations

Cost-effectiveness of population based BRCA testing with varying Ashkenazi Jewish ancestry

BACKGROUND: Population-based BRCA1/BRCA2 testing has been found to be cost-effective compared with family history-based testing in Ashkenazi-Jewish women were >30 years old with 4 Ashkenazi-Jewish grandparents. However, individuals may have 1, 2, or 3 Ashkenazi-Jewish grandparents, and cost-effectiveness data are lacking at these lower BRCA prevalence estimates. We present an updated cost-effectiveness analysis of population BRCA1/BRCA2 testing for women with 1, 2, and 3 Ashkenazi-Jewish grandparents. METHODS: Lifetime costs and effects of population and family history-based testing were compared with the use of a decision analysis model: 56% BRCA carriers are missed by family history criteria alone. Analyses were conducted for United Kingdom and United States populations. STUDY DESIGN: Model parameters were obtained from the Genetic Cancer Prediction through Population Screening trial and published literature. Model parameters and BRCA population prevalence for individuals with 3, 2, or 1 Ashkenazi-Jewish grandparent were adjusted for the relative frequency of BRCA mutations in the Ashkenazi-Jewish and general populations. Incremental cost-effectiveness ratios were calculated for all Ashkenazi-Jewish grandparent scenarios. Costs, along with outcomes, were discounted at 3.5%. The time horizon of the analysis is "life-time," and perspective is "payer." Probabilistic sensitivity analysis evaluated model uncertainty. RESULTS: Population testing for BRCA mutations is cost-saving in Ashkenazi-Jewish women with 2, 3, or 4 grandparents (22-33 days life-gained) in the United Kingdom and 1, 2, 3, or 4 grandparents (12-26 days life-gained) in the United States populations, respectively. It is also extremely cost-effective in women in the United Kingdom with just 1 Ashkenazi-Jewish grandparent with an incremental cost-effectiveness ratio of £863 per quality-adjusted life-years and 15 days life gained. Results show that population-testing remains cost-effective at the £20,000-30000 per quality-adjusted life-years and $100,000 per quality-adjusted life-years willingness-to-pay thresholds for all 4 Ashkenazi-Jewish grandparent scenarios, with ≥95% simulations found to be cost-effective on probabilistic sensitivity analysis. Population-testing remains cost-effective in the absence of reduction in breast cancer risk from oophorectomy and at lower risk-reducing mastectomy (13%) per risk-reducing salpingo-oophorectomy (20%) rates. CONCLUSION: Population testing for BRCA mutations with varying levels of Ashkenazi-Jewish ancestry is cost-effective in the United Kingdom and the United States. These results support population testing in Ashkenazi-Jewish women with 1-4 Ashkenazi-Jewish grandparent ancestry.Supported by “The Eve Appeal” charity, which had no role in the study design, data collection, analysis, interpretation, writing of the report, or decision to submit for publication. The research team was independent of funders. I.J. and U.M. have a financial interest in Abcodia, Ltd, which is a company formed to develop academic and commercial development of biomarkers for screening and risk prediction; I.J. is a member of the board of Abcodia Ltd and a Director of Women’s Health Specialists Ltd. R.M. declares funding for research from Cancer Research UK and Barts and the London Charity outside this submitted work and an honorarium for grant review from Israel National institute for Health Policy Research. The other authors declare no conflict of interest