Engaging 'hard to reach' groups in health promotion: the views of older people and professionals from a qualitative study in England.

BACKGROUND: Older people living in deprived areas, from black and minority ethnic groups (BME) or aged over 85 years (oldest old) are recognised as 'hard to reach'. Engaging these groups in health promotion is of particular importance when seeking to target those who may benefit the most and to reduce health inequalities. This study aimed to explore what influences them practicing health promotion and elicit the views of cross-sector professionals with experiences of working with 'hard to reach' older people, to help inform best practice on engagement. METHODS: 'Hard to reach' older people were recruited through primary care by approaching those not attending for preventative healthcare, and via day centres. Nineteen participated in an interview (n = 15) or focus group (n = 4); including some overlaps: 17 were from a deprived area, 12 from BME groups, and five were oldest old. Cross-sector health promotion professionals across England with experience of health promotion with older people were identified through online searches and snowball sampling. A total of 31 of these 44 professionals completed an online survey including open questions on barriers and facilitators to uptake in these groups. Thematic analysis was used to develop a framework of higher and lower level themes. Interpretations were discussed and agreed within the team. RESULTS: Older people's motivation to stay healthy and independent reflected their everyday behaviour including practicing activities to feel or stay well, level of social engagement, and enthusiasm for and belief in health promotion. All of the oldest old reported trying to live healthily, often facilitated by others, yet sometimes being restricted due to poor health. Most older people from BME groups reported a strong wish to remain independent which was often positively influenced by their social network. Older people living in deprived areas reported reluctance to undertake health promotion activities, conveyed apathy and reported little social interaction. Cross-sector health professionals consistently reported similar themes as the older people, reinforcing the views of the older people through examples. CONCLUSIONS: The study shows some shared themes across the three 'hard-to-reach' groups but also some distinct differences, suggesting that a carefully outlined strategy should be considered to reach successfully the group targeted.

Health promotion interventions for community-dwelling older people with mild or pre-frailty: a systematic review and meta-analysis.

BACKGROUND: Mild or pre-frailty is common and associated with increased risks of hospitalisation, functional decline, moves to long-term care, and death. Little is known about the effectiveness of health promotion in reducing these risks. This systematic review aimed to synthesise randomised controlled trials (RCTs) evaluating home and community-based health promotion interventions for older people with mild/pre-frailty. METHODS: We searched 20 bibliographic databases and 3 trials registers (January 1990 - May 2016) using mild/pre-frailty and associated terms. We included randomised controlled and crossover trials of health promotion interventions for community-dwelling older people (65+ years) with mild/pre-frailty and excluded studies focussing on populations in hospital, long term care facilities or with a specific condition. Risk of bias was assessed by two reviewers using the Cochrane Risk of Bias tool. We pooled study results using standardised mean differences (SMD) where possible and used narrative synthesis where insufficient outcome data were available. RESULTS: We included 10 articles reporting on seven trials (total n = 506 participants) and included five trials in a meta-analysis. Studies were predominantly small, of limited quality and six studies tested group exercise alone. One study additionally investigated a nutrition and exercise intervention and one evaluated telemonitoring. Interventions of exercise in groups showed mixed effects on functioning (no effects on self-reported functioning SMD 0.19 (95% CI -0.57 to 0.95) n = 3 studies; positive effects on performance-based functioning SMD 0.37 (95% CI 0.07 to 0.68) n = 3 studies). No studies assessed moves to long-term care or hospitalisations. CONCLUSIONS: Currently the evidence base is of insufficient size, quality and breadth to recommend specific health promotion interventions for older people with mild or pre- frailty. High quality studies of rigorously developed interventions are needed. PROSPERO REGISTRATION: CRD42014010370 (Review 2).

Strategies to improve engagement of 'hard to reach' older people in research on health promotion: a systematic review.

BACKGROUND: This systematic review aimed to identify facilitators, barriers and strategies for engaging 'hard to reach' older people in research on health promotion; the oldest old (≥80 years), older people from black and minority ethnic groups (BME) and older people living in deprived areas. METHODS: Eight databases were searched to identify eligible studies using quantitative, qualitative, and mixed research methods. Using elements of narrative synthesis, engagement strategies, and reported facilitators and barriers were identified, tabulated and analysed thematically for each of the three groups of older people. RESULTS: Twenty-three studies (3 with oldest-old, 16 with BME older people, 2 within deprived areas, 1 with both oldest-old and BME, 1 with both BME and deprived areas) were included. Methods included 10 quantitative studies (of which 1 was an RCT), 12 qualitative studies and one mixed-methods study. Facilitators for engaging the oldest old included gaining family support and having flexible sessions. Facilitators for BME groups included building trust through known professionals/community leaders, targeting personal interests, and addressing ethnic and cultural characteristics. Among older people in deprived areas, facilitators for engagement included encouragement by peers and providing refreshments. Across all groups, barriers for engagement were deteriorating health, having other priorities and lack of transport/inaccessibility. Feeling too tired and lacking support from family members were additional barriers for the oldest old. Similarly, feeling too tired and too old to participate in research on health promotion were reported by BME groups. Barriers for BME groups included lack of motivation and self-confidence, and cultural and language differences. Barriers identified in deprived areas included use of written recruitment materials. Strategies to successfully engage with the oldest old included home visits and professionals securing consent if needed. Strategies to engage older people from BME groups included developing community connections and organising social group sessions. Strategies to engage with older people in deprived areas included flexibility in timing and location of interventions. CONCLUSIONS: This review identified facilitators, barriers and strategies for engaging 'hard to reach' older people in health promotion but research has been mainly descriptive and there was no high quality evidence on the effectiveness of different approaches.

Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic factors and pathology. On the cellular level, a majority of ALS and FTD cases are characterized by nuclear clearance and cytoplasmic aggregation of otherwise nuclear proteins, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma. Recent studies investigating cellular pathways perturbed by genetic risk factors for ALS/FTD converge on nucleocytoplasmic transport dysfunction as a mechanism leading to disease pathophysiology. We propose that mutations in FUS and hexanucleotide expansions in C9orf72 and aging all converge on the impairment of nucleocytoplasmic transport, which results in the hallmark pathological feature of ALS/FTD - cytoplasmic aggregation of TDP-43 or FUS.

The novel Parkinson's disease linked mutation G51D attenuates in vitro aggregation and membrane binding of α-synuclein, and enhances its secretion and nuclear localization in cells.

A novel mutation in the α-Synuclein (α-Syn) gene "G51D" was recently identified in two familial cases exhibiting features of Parkinson's disease (PD) and multiple system atrophy (MSA). In this study, we explored the impact of this novel mutation on the aggregation, cellular and biophysical properties of α-Syn, in an attempt to unravel how this mutant contributes to PD/MSA. Our results show that the G51D mutation significantly attenuates α-Syn aggregation in vitro. Moreover, it disrupts local helix formation in the presence of SDS, decreases binding to lipid vesicles C-terminal to the site of mutation and severely inhibits helical folding in the presence of acidic vesicles. When expressed in yeast, α-Syn(G51D) behaves similarly to α-Syn(A30P), as both exhibit impaired membrane association, form few inclusions and are non-toxic. In contrast, enhanced secreted and nuclear levels of the G51D mutant were observed in mammalian cells, as well as in primary neurons, where α-Syn(G51D) was enriched in the nuclear compartment, was hyper-phosphorylated at S129 and exacerbated α-Syn-induced mitochondrial fragmentation. Finally, post-mortem human brain tissues of α-Syn(G51D) cases were examined, and revealed only partial colocalization with nuclear membrane markers, probably due to post-mortem tissue delay and fixation. These findings suggest that the PD-linked mutations may cause neurodegeneration via different mechanisms, some of which may be independent of α-Syn aggregation.

Healthy eating habits among the population of Serbia: gender and age differences.

The purpose of the study is to examine healthy eating habits of the population of Serbia through three dimensions: knowledge, problems, and feelings as well as to determine whether there are any differences between genders and among different age-groups. The research instrument was an Eating Habits Questionnaire (EHQ) which consisted of 35 items. There were 382 respondents involved in the study. The reliability and factor structure of the questionnaire were verified by using factor analysis. The results of MANOVA showed that there is a significant difference in the habits concerning healthy eating between men and women [F (3,378)=4.26, p=0.006; Wilks' Lambda=0.97]. When the results for the dependent variables (knowledge, problems, and feelings) were considered separately, it was determined that there is no significant difference between men and women, which confirms the results of the t-test. The effect of age on the three dimensions of healthy eating habits was examined within three age-groups, by using ANOVA. The results showed that knowledge about healthy eating increases with age [F (2,379)=6.14, p=0.002] as well as positive feelings which occur as a result of healthy eating [F (2,379)=3.66, p=0.027]. Unlike ANOVA, MANOVA showed difference among the age-groups only when it came to the 'knowledge' variable. This study is important as it shows the current state of awareness on healthy eating habits in the researched populace and may be the basis for further research in this field in Serbia.

Comprehensive expression analyses of neural cell-type-specific miRNAs identify new determinants of the specification and maintenance of neuronal phenotypes.

MicroRNAs (miRNAs) have been shown to play important roles in both brain development and the regulation of adult neural cell functions. However, a systematic analysis of brain miRNA functions has been hindered by a lack of comprehensive information regarding the distribution of miRNAs in neuronal versus glial cells. To address this issue, we performed microarray analyses of miRNA expression in the four principal cell types of the CNS (neurons, astrocytes, oligodendrocytes, and microglia) using primary cultures from postnatal d 1 rat cortex. These analyses revealed that neural miRNA expression is highly cell-type specific, with 116 of the 351 miRNAs examined being differentially expressed fivefold or more across the four cell types. We also demonstrate that individual neuron-enriched or neuron-diminished RNAs had a significant impact on the specification of neuronal phenotype: overexpression of the neuron-enriched miRNAs miR-376a and miR-434 increased the differentiation of neural stem cells into neurons, whereas the opposite effect was observed for the glia-enriched miRNAs miR-223, miR-146a, miR-19, and miR-32. In addition, glia-enriched miRNAs were shown to inhibit aberrant glial expression of neuronal proteins and phenotypes, as exemplified by miR-146a, which inhibited neuroligin 1-dependent synaptogenesis. This study identifies new nervous system functions of specific miRNAs, reveals the global extent to which the brain may use differential miRNA expression to regulate neural cell-type-specific phenotypes, and provides an important data resource that defines the compartmentalization of brain miRNAs across different cell types.

To support and not to cure: general practitioner management of loneliness.

Loneliness is associated with numerous detrimental effects on physical health, mental health, cognition and lifestyle. Older adults are one of the groups at highest risk of loneliness, and indeed about 46% of older adults in England feel lonely. Those experiencing loneliness visit their general practitioner (GP) more frequently than those who are not, which has the capacity to put a strain on GPs and primary care waiting lists and costs. This study's aim was to explore GPs' views and experiences of loneliness within their older adult patients, and to understand GPs' awareness and feelings of agency within this. Nineteen UK GPs were recruited using purposive sampling and snowballing techniques. Individual semi-structured interviews were conducted either in person or over the telephone. Data were analysed using thematic analysis. Four overarching themes were identified from the data: Whose responsibility is it anyway?, Pandora's box of shame; Keeping distance; and Community responsibility. Themes emphasise that GPs tend to hold a medicalised and individualistic view of loneliness. This intensifies stigma which in turn creates barriers to raising the topic. GPs felt powerless in their ability to fix the 'problem' and tended to believe that the solution had to lie in the community, the individual or in social care rather than in primary care. The findings are discussed in the context of literature on GP management of other social problems which give rise to similar issues concerning the restrictions of the medical model and the need for joined-up approaches in which the GP is one part of a wider social support structure. It is suggested that it might be useful for training and support for GPs to address management of social problems jointly rather than training specific to loneliness which GPs tend to see as peripheral to their core remit.

Heterogeneity of Satellite Cells Implicates DELTA1/NOTCH2 Signaling in Self-Renewal.

How satellite cells and their progenitors balance differentiation and self-renewal to achieve sustainable tissue regeneration is not well understood. A major roadblock to understanding satellite cell fate decisions has been the difficulty of studying this process in vivo. By visualizing expression dynamics of myogenic transcription factors during early regeneration in vivo, we identify the time point at which cells undergo decisions to differentiate or self-renew. Single-cell RNA sequencing reveals heterogeneity of satellite cells, including a subpopulation enriched in Notch2 receptor expression, during both muscle homeostasis and regeneration. Furthermore, we reveal that differentiating cells express the Dll1 ligand. Using antagonistic antibodies, we demonstrate that the DLL1 and NOTCH2 signaling pair is required for satellite cell self-renewal. Thus, differentiating cells provide the self-renewing signal during regeneration, enabling proportional regeneration in response to injury while maintaining the satellite cell pool. These findings have implications for therapeutic control of muscle regeneration.

Identifying acceptable components for home-based health promotion services for older people with mild frailty: A qualitative study.

Mild frailty is common in later life, increasing the risk of hospitalisation, loss of independence and premature death. Targeted health promotion services may reduce adverse outcomes and increase quality of life; however, effective, well-developed theory-based interventions are lacking. We aimed to explore perceptions of health promotion behaviours undertaken by older people with mild frailty, barriers and facilitators to engagement, and identify potential components for new home-based health promotion services. We carried out 17 semi-structured qualitative interviews and six focus groups with 53 stakeholders, including 14 mildly frail older people, 12 family carers, 19 community health and social care professionals, and 8 homecare workers, in one urban and one semi-rural area of England. Transcripts were thematically analysed. Older people with mild frailty reported engaging in a variety of lifestyle behaviours to promote health and well-being. Key barriers or facilitators to engaging in these included transport, knowledge of local services, social support and acceptance of personal limitations. Older people, carers and professionals agreed that any new service should address social networks and mobility and tailor other content to each individual. Services should aim to increase motivation through focussing on independence and facilitate older people to continue carrying out behaviours that improve their well-being, as well as provide information, motivation, psychological support and practical support. Stakeholders agreed services should be delivered over a sustained period by trained non-specialist workers. New services including these components are likely to be acceptable to older people with mild frailty.

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases.

Distinct repertoires of microRNAs present in mouse astrocytes compared to astrocyte-secreted exosomes.

BACKGROUND: Astrocytes are the most abundant cell type in the central nervous system (CNS) and secrete various factors that regulate neuron development, function and connectivity. microRNAs (miRNAs) are small regulatory RNAs involved in posttranslational gene regulation. Recent findings showed that miRNAs are exchanged between cells via nanovesicles called exosomes. In this study, we sought to define which miRNAs are contained within exosomes secreted by astrocytes. We also explored whether astroglial miRNA secretion via exosomes is perturbed in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease where astrocytes play a crucial role in driving disease progression. METHODOLOGY/PRINCIPAL FINDINGS: By isolating and profiling the expression of miRNAs from primary mouse astrocytes and from the exosomes that astrocytes secrete, we compared miRNA expression in the cells and secreted vesicles. We established that miRNA expression profiles of astrocytes and their exosomes are vastly different. In addition, we determined that exosomal miRNA expression in astrocytes is not significantly perturbed in a mouse model of ALS. CONCLUSIONS: Astrocytes secrete numerous miRNAs via exosomes and miRNA species contained in exosomes are considerably different from miRNAs detectable in astrocytes, suggesting the existence of a mechanism to select certain miRNAs for inclusion or exclusion from exosomes. The exosomal miRNA profiling dataset we have generated will provide a resource to aid in the investigation of this selection mechanism. Finally, the miRNA expression profile in astrocyte-secreted exosomes is not perturbed by expression of mutant SOD1-G93A.

Specifying the content of home-based health behaviour change interventions for older people with frailty or at risk of frailty: an exploratory systematic review.

OBJECTIVES: To identify trials of home-based health behaviour change interventions for frail older people, describe intervention content and explore its potential contribution to intervention effects. DESIGN: 15 bibliographic databases, and reference lists and citations of key papers, were searched for randomised controlled trials of home-based behavioural interventions reporting behavioural or health outcomes. SETTING: Participants' homes. PARTICIPANTS: Community-dwelling adults aged ≥65 years with frailty or at risk of frailty. PRIMARY AND SECONDARY OUTCOME MEASURES: Trials were coded for effects on thematically clustered behavioural, health and well-being outcomes. Intervention content was described using 96 behaviour change techniques, and 9 functions (eg, education, environmental restructuring). RESULTS: 19 eligible trials reported 22 interventions. Physical functioning was most commonly assessed (19 interventions). Behavioural outcomes were assessed for only 4 interventions. Effectiveness on most outcomes was limited, with at most 50% of interventions showing potential positive effects on behaviour, and 42% on physical functioning. 3 techniques (instruction on how to perform behaviour, adding objects to environment, restructuring physical environment) and 2 functions (education and enablement) were more commonly found in interventions showing potential than those showing no potential to improve physical function. Intervention content was not linked to effectiveness on other outcomes. CONCLUSIONS: Interventions appeared to have greatest impact on physical function where they included behavioural instructions, environmental modification and practical social support. Yet, mechanisms of effects are unclear, because impact on behavioural outcomes has rarely been considered. Moreover, the robustness of our findings is also unclear, because interventions have been poorly reported. Greater engagement with behavioural science is needed when developing and evaluating home-based health interventions. PROSPERO REGISTRATION NUMBER: ID=CRD42014010370.

Home-based health promotion for older people with mild frailty: the HomeHealth intervention development and feasibility RCT.

BACKGROUND: Mild frailty or pre-frailty is common and yet is potentially reversible. Preventing progression to worsening frailty may benefit individuals and lower health/social care costs. However, we know little about effective approaches to preventing frailty progression. OBJECTIVES: (1) To develop an evidence- and theory-based home-based health promotion intervention for older people with mild frailty. (2) To assess feasibility, costs and acceptability of (i) the intervention and (ii) a full-scale clinical effectiveness and cost-effectiveness randomised controlled trial (RCT). DESIGN: Evidence reviews, qualitative studies, intervention development and a feasibility RCT with process evaluation. INTERVENTION DEVELOPMENT: Two systematic reviews (including systematic searches of 14 databases and registries, 1990-2016 and 1980-2014), a state-of-the-art review (from inception to 2015) and policy review identified effective components for our intervention. We collected data on health priorities and potential intervention components from semistructured interviews and focus groups with older people (aged 65-94 years) (n = 44), carers (n = 12) and health/social care professionals (n = 27). These data, and our evidence reviews, fed into development of the 'HomeHealth' intervention in collaboration with older people and multidisciplinary stakeholders. 'HomeHealth' comprised 3-6 sessions with a support worker trained in behaviour change techniques, communication skills, exercise, nutrition and mood. Participants addressed self-directed independence and well-being goals, supported through education, skills training, enabling individuals to overcome barriers, providing feedback, maximising motivation and promoting habit formation. FEASIBILITY RCT: Single-blind RCT, individually randomised to 'HomeHealth' or treatment as usual (TAU). SETTING: Community settings in London and Hertfordshire, UK. PARTICIPANTS: A total of 51 community-dwelling adults aged ≥ 65 years with mild frailty. MAIN OUTCOME MEASURES: Feasibility - recruitment, retention, acceptability and intervention costs. Clinical and health economic outcome data at 6 months included functioning, frailty status, well-being, psychological distress, quality of life, capability and NHS and societal service utilisation/costs. RESULTS: We successfully recruited to target, with good 6-month retention (94%). Trial procedures were acceptable with minimal missing data. Individual randomisation was feasible. The intervention was acceptable, with good fidelity and modest delivery costs (£307 per patient). A total of 96% of participants identified at least one goal, which were mostly exercise related (73%). We found significantly better functioning (Barthel Index +1.68; p = 0.004), better grip strength (+6.48 kg; p = 0.02), reduced psychological distress (12-item General Health Questionnaire -3.92; p = 0.01) and increased capability-adjusted life-years [+0.017; 95% confidence interval (CI) 0.001 to 0.031] at 6 months in the intervention arm than the TAU arm, with no differences in other outcomes. NHS and carer support costs were variable but, overall, were lower in the intervention arm than the TAU arm. The main limitation was difficulty maintaining outcome assessor blinding. CONCLUSIONS: Evidence is lacking to inform frailty prevention service design, with no large-scale trials of multidomain interventions. From stakeholder/public perspectives, new frailty prevention services should be personalised and encompass multiple domains, particularly socialising and mobility, and can be delivered by trained non-specialists. Our multicomponent health promotion intervention was acceptable and delivered at modest cost. Our small study shows promise for improving clinical outcomes, including functioning and independence. A full-scale individually RCT is feasible. FUTURE WORK: A large, definitive RCT of the HomeHealth service is warranted. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014010370 and Current Controlled Trials ISRCTN11986672. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 73. See the NIHR Journals Library website for further project information.

Semisynthetic and in Vitro Phosphorylation of Alpha-Synuclein at Y39 Promotes Functional Partly Helical Membrane-Bound States Resembling Those Induced by PD Mutations.

Alpha-synuclein is a presynaptic protein of poorly understood function that is linked to both genetic and sporadic forms of Parkinson's disease. We have proposed that alpha-synuclein may function specifically at synaptic vesicles docked at the plasma membrane, and that the broken-helix state of the protein, comprising two antiparallel membrane-bound helices connected by a nonhelical linker, may target the protein to such docked vesicles by spanning between the vesicle and the plasma membrane. Here, we demonstrate that phosphorylation of alpha-synuclein at tyrosine 39, carried out by c-Abl in vivo, may facilitate interconversion of synuclein from the vesicle-bound extended-helix state to the broken-helix state. Specifically, in the presence of lipid vesicles, Y39 phosphorylation leads to decreased binding of a region corresponding to helix-2 of the broken-helix state, potentially freeing this region of the protein to interact with other membrane surfaces. This effect is largely recapitulated by the phosphomimetic mutation Y39E, and expression of this mutant in yeast results in decreased membrane localization. Intriguingly, the effects of Y39 phosphorylation on membrane binding closely resemble those of the recently reported disease linked mutation G51D. These findings suggest that Y39 phosphorylation could modulate functional aspects of alpha-synuclein and perhaps influence pathological aggregation of the protein as well.

Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD.

Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.

Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis.

Persistent accumulation of misfolded proteins causes endoplasmic reticulum (ER) stress, a prominent feature in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here we report the identification of homeodomain interacting protein kinase 2 (HIPK2) as the essential link that promotes ER-stress-induced cell death via the IRE1α-ASK1-JNK pathway. ER stress, induced by tunicamycin or SOD1(G93A), activates HIPK2 by phosphorylating highly conserved serine and threonine residues (S359/T360) within the activation loop of the HIPK2 kinase domain. In SOD1(G93A) mice, loss of HIPK2 delays disease onset, reduces cell death in spinal motor neurons, mitigates glial pathology, and improves survival. Remarkably, HIPK2 activation positively correlates with TDP-43 proteinopathy in NEFH-tTA/tetO-hTDP-43ΔNLS mice, sporadic ALS and C9ORF72 ALS, and blocking HIPK2 kinase activity protects motor neurons from TDP-43 cytotoxicity. These results reveal a previously unrecognized role of HIPK2 activation in ER-stress-mediated neurodegeneration and its potential role as a biomarker and therapeutic target for ALS. VIDEO ABSTRACT.

Identifying the content of home-based health behaviour change interventions for frail older people: a systematic review protocol.

BACKGROUND: Meeting the needs of the growing number of older people is a challenge for health and social care services. Home-based interventions aiming to modify health-related behaviours of frail older people have the potential to improve functioning and well-being. Previous reviews have focused on whether such interventions are effective, rather than what might make them effective. Recent advances in behavioural science make possible the identification of potential 'active ingredients' of effective interventions, such as component behaviour change techniques (BCTs), and intended intervention functions (IFs; e.g. to educate, to impart skills). This paper reports a protocol for a systematic review that seeks to (a) identify health behaviour change interventions for older frail people, (b) describe the content of these interventions, and (c) explore links between intervention content and effectiveness. The protocol is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) 2015 guidelines. METHODS/DESIGN: Studies will be identified through a systematic search of 15 electronic databases, supplemented by citation tracking. Studies will be retained for review where they report randomised controlled trials focusing on home-based health promotion delivered by a health professional for frail older people in community settings, written in English, and either published from 1980 onwards, or, for registered trials only, unpublished but completed with results obtainable from authors. Interventions will be coded for their content (BCTs, IFs) and for evidence of effectiveness (outcome data relating to behavioural and health outcomes). Analyses will describe characteristics of all interventions. Interventions for which effectiveness data are available will be categorised into those showing evidence of effectiveness versus those showing no such evidence. The potential for each intervention characteristic to contribute to change in behaviour or health outcomes will be estimated by calculating the percentage of all interventions featuring those characteristics that have shown effectiveness. DISCUSSION: Results will reveal the strategies that have been drawn on within home-based interventions to modify the health behaviours of frail older people, and highlight those more associated with positive changes in behaviour and health. Findings from this review will provide a useful basis for understanding, developing, and implementing behaviour change interventions in this field. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014010370.

Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS.

C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.

TDP-43 in ALS: stay on target almost there.

ALS is associated with RNA processing impairments involving the RNA-binding protein TDP-43. Pioneering a novel RNA beacon to illuminate RNA trafficking in neurons, Alami et al. (2014) discover a cytoplasmic function for TDP-43, suggesting a new disease mechanism.