Regulation of LRRK2 Stability by the E3 Ubiquitin Ligase CHIP

Dominantly inherited mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common cause of familial Parkinson's disease (PD) and have also been identified in individuals with sporadic PD. Although the exact cellular function of LRRK2 remains unknown, most PD-linked mutations appear to be toxic to cells in culture via mechanisms that depend on the kinase activity of LRRK2 or on the formation of cytoplasmic inclusions. Here we show that the E3 ubiquitin ligase CHIP physically associates with LRRK2 and regulates the cellular abundance of LRRK2. We further show that LRRK2 forms a complex with overexpressed and endogenous CHIP and Hsp90. Our data indicates that the destabilization of LRRK2 by CHIP is due to ubiquitination and proteasome-dependent degradation. Hsp90 can attenuate CHIP-mediated degradation and this can be blocked by the Hsp90 inhibitor geldanamycin. These findings provide important insight into the cellular regulation of LRRK2 stability and may lead to the development of therapeutics to treat PD based on controlling LRRK2 stability

Understanding the relationship between income and mental health among 16- to 24-year-olds: Analysis of 10 waves (2009-2020) of Understanding Society to enable modelling of income interventions

A substantial body of evidence suggests that young people, including those at the crucial transition points between 16 and 24, now face severe mental health challenges. In this article, we analyse data from 10 waves of a major UK longitudinal household cohort study, Understanding Society, to examine the relationship between income and anxiety and depression among 16- to 24-year-olds. Using random effects logistic regression (Model 1) allowing for whether the individual was depressed in the previous period as well as sex, age, ethnicity, whether the individual was born in the UK, region, rurality, highest qualification, marital status, employment status and attrition, we find a significant and inversely monotonic adjusted association between average net equivalised household income quintiles and clinical threshold levels of depressive symptoms SF-12 Mental Component Summary (MCS score ≤45.6). This means that being in a higher income group is associated with a reduced likelihood of clinically significant depressive symptoms, allowing for observable confounding variables. Using a ‘within-between’ model (Model 2), we find that apart from among those with the very highest incomes, increases in average net equivalised household income over the course of childhood and adolescence are significantly associated with reduced symptoms of anxiety and depression as measured by a higher SF-12 MCS score. Compared with previous reviews, the data presented here provides an estimate of the magnitude of effect that helps facilitate microsimulation modelling of impact on anxiety and depression from changes in socioeconomic circumstances. This enables a more detailed and complete understanding of the types of socioeconomic intervention that might begin to address some of the causes of youth mental health problems

Years of good life based on income and health: re-engineering cost-benefit analysis to examine policy impacts on wellbeing and distributive justice

In this paper, we propose a practical measure of individual wellbeing to facilitate the economic evaluation of public policies. We propose to evaluate policies in terms of years of good life gained, in a way that complements and generalises conventional cost-benefit analysis in terms of money. We aim to show how years of good life could be measured in practice by harnessing readily available data on three important elements of individual wellbeing: income, health-related quality of life, and longevity. We also aim to identify the main ethical assumptions needed to use this measure

Understanding the relationship between income and mental health among 16- to 24-year-olds : Analysis of 10 waves (2009–2020) of Understanding Society to enable modelling of income interventions

A substantial body of evidence suggests that young people, including those at the crucial transition points between 16 and 24, now face severe mental health challenges. In this article, we analyse data from 10 waves of a major UK longitudinal household cohort study, Understanding Society, to examine the relationship between income and anxiety and depression among 16- to 24-year-olds. Using random effects logistic regression (Model 1) allowing for whether the individual was depressed in the previous period as well as sex, age, ethnicity, whether the individual was born in the UK, region, rurality, highest qualification, marital status, employment status and attrition, we find a significant and inversely monotonic adjusted association between average net equivalised household income quintiles and clinical threshold levels of depressive symptoms SF-12 Mental Component Summary (MCS score ≤45.6). This means that being in a higher income group is associated with a reduced likelihood of clinically significant depressive symptoms, allowing for observable confounding variables. Using a ‘within-between’ model (Model 2), we find that apart from among those with the very highest incomes, increases in average net equivalised household income over the course of childhood and adolescence are significantly associated with reduced symptoms of anxiety and depression as measured by a higher SF-12 MCS score. Compared with previous reviews, the data presented here provides an estimate of the magnitude of effect that helps facilitate microsimulation modelling of impact on anxiety and depression from changes in socioeconomic circumstances. This enables a more detailed and complete understanding of the types of socioeconomic intervention that might begin to address some of the causes of youth mental health problems

Evidence of Immune Modulators in the Secretome of the Equine Tapeworm Anoplocephala perfoliata

Anoplocephala perfoliata is a neglected gastro-intestinal tapeworm, commonly infecting horses worldwide. Molecular investigation of A. perfoliata is hampered by a lack of tools to better understand the host–parasite interface. This interface is likely influenced by parasite derived immune modulators released in the secretome as free proteins or components of extracellular vesicles (EVs). Therefore, adult RNA was sequenced and de novo assembled to generate the first A. perfoliata transcriptome. In addition, excretory secretory products (ESP) from adult A. perfoliata were collected and EVs isolated using size exclusion chromatography, prior to proteomic analysis of the EVs, the EV surface and EV depleted ESP. Transcriptome analysis revealed 454 sequences homologous to known helminth immune modulators including two novel Sigma class GSTs, five α-HSP90s, and three α-enolases with isoforms of all three observed within the proteomic analysis of the secretome. Furthermore, secretome proteomics identified common helminth proteins across each sample with known EV markers, such as annexins and tetraspanins, observed in EV fractions. Importantly, 49 of the 454 putative immune modulators were identified across the secretome proteomics contained within and on the surface of EVs in addition to those identified in free ESP. This work provides the molecular tools for A. perfoliata to reveal key players in the host–parasite interaction within the horse host