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An expanded repetition of a DNA sequence within the C9orf72 gene is the most common genetic cause for motor neuron disease and frontotemporal dementia. In this study, the authors show that this expansion causes increased genomic breaks and reduces the cell's ability to repair the breaks, ultimately leading to neuronal cell death. Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA–RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus-mediated expression of C9 orf 72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. These findings identify R-loops, double strand breaks and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72 -linked neurodegeneration is driven at least partly by genomic instability.

Intronic GGGGCC repeat expansions in are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, although it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here, we describe two novel lines of mice that overexpress either 10 pure or 102 interrupted GGGGCC repeats mediated by adeno-associated virus (AAV) and recapitulate the relevant human pathology and disease-related behavioural phenotypes. Similar levels of intracellular RNA foci developed in both lines of mice, but only mice expressing 102 repeats generated RAN pathology, neuromuscular junction (NMJ) abnormalities, dispersal of the hippocampal CA1, enhanced apoptosis, and deficits in gait and cognition. Neither line of mice, however, showed extensive TAR DNA-binding protein 43 (TDP-43) pathology or neurodegeneration. Our data suggest that RNA foci pathology is not a good predictor of RAN dipeptide formation, and that RAN dipeptides and NMJ dysfunction are drivers of disease pathogenesis. These AAV-mediated models of -associated ALS/FTD will be useful tools for studying disease pathophysiology and developing new therapeutic approaches.

Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, though it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here we generated two novel lines of mice that overexpress either 10 pure or 102 interrupted G4C2 repeats mediated by adeno-associated virus (AAV) and characterized relevant pathology and disease-related behavioral phenotypes. Similar levels of intracellular RNA foci developed in both lines of mice, but only mice expressing 102 repeats generated c9-RAN pathology, neuromuscular junction (NMJ) abnormalities, dispersal of the hippocampal CA1, enhanced apoptosis, and deficits in gait and cognition. Neither line of mice, however, showed extensive TAR DNA-binding protein 43 (TDP-43) pathology or neurodegeneration. Our data suggests that RNA foci pathology is not a good predictor of c9-RAN dipeptide formation, and that RAN dipeptides and NMJ dysfunction are drivers of c9-disease pathogenesis. These AAV-mediated models of C9orf72 ALS/FTD will be useful tools for studying disease pathophysiology and developing new therapeutic approaches.

Abstract Purpose Combined exercise and dietary interventions have been shown to benefit older adults with frailty, with significant promise in transitioning between frailty states. However, there is limited availability of such interventions, partly due to a lack of capacity in healthcare. While community-based programmes offer a plausible solution, often intervention settings do not reflect the transfer of research to practical ‘real world’ programmes and there is a paucity of research investigating ‘true’ community-based programmes. With older adults citing numerous barriers to adherence, the purpose of this study was to describe the development of DEFRAIL (Diet and Exercise for Frailty), a patient-centred, evidenced-based behaviour change intervention. Methods The research is guided by the Medical Research Council’s Framework for the Development, Evaluation, and Implementation of Complex Interventions. Four key steps contributed to the intervention development. 1) A review of the literature identified the evidence for intervention delivery models. 2) Interviews with older adults with frailty (n = 13) explored attitudes and preferences for exercise and protein supplementation. 3) A behaviour change analysis was performed using the COM-B Model to identify behaviour change techniques (BCTs) to embed in the intervention. 4) An expert panel of healthcare professionals, academics and potential implementers (n = 18) was consulted, via a DELPHI process to obtain consensus on the final structure of the intervention. Results There is a lack of detail on intervention delivery models in the literature. Settings varied for ‘community’ interventions from universities, research centres, gym and home-based programmes. Three key themes were identified from the interviews with older adults: impact of physical limitations, impact of knowledge, impact of medical professionals, which influenced capability, opportunity, and motivation in regards to the behaviours. Modifiable barriers identified, informed the selection of intervention functions and BCTs, which were translated into actionable intervention components. The expert panel agreed the final components of the intervention. Conclusion Developing interventions underpinned by evidence, theory and with input from end-users and experts will enhance the potential for positive behaviour change, promoting adherence to the intervention and hence, increase its potential effectiveness. Support/Funding Source This study is funded by the Irish Research Council enterprise partner scholarship with industry partner Tírlan.

IntroductionFrailty refers to a multifaceted age-related loss of physiological reserve. Aside from the immediate challenges it presents, it is also associated with various adverse health outcomes. Given our ageing population, the healthcare and societal costs resulting from frailty present a significant and growing public health challenge. Rapidly accumulating evidence suggests that resistance exercise combined with protein supplementation can reverse frailty in older adults. However, translation of these findings into practice has proven difficult, due to either a lack of clarity regarding the interventions used or the use of interventions not suitable for widespread implementation. There remains an absence of evidence-based programmes suitable for delivery to frail older adults in the community.Methods and analysisThis paper outlines the protocol for a study to examine the effect of a novel programme of exercise and protein supplementation. This intervention has been developed by an expert consensus group, specifically for delivery to frail older adults in a group setting in the community. The study will take the form of a within-subjects non-randomised trial. Participants will be assessed at baseline, then following an 8-week period of regular activity, then following the 8-week intervention. Frailty (according to the Fried Frailty criteria) will be the primary outcome measure, along with a range of secondary outcome measures (including physical performance measures, body mass composition, psychosocial assessments and frailty-related biomarkers). If shown to be feasible to implement and effective at reversing frailty, the Diet and Exercise for FRAILty (DEFRAIL) intervention may facilitate more widespread participation in resistance exercise for frail older adults.Ethics and disseminationThis study received ethical approval from the Research Ethics committees of both the Health Service Executive South-Eastern Area and Waterford Institute of Technology. Its findings will be disseminated through journal publications, conference presentations and other forms of public engagement.Trial registration numberISRCTN46458028; Pre-results.

Background: Monitoring of human exposure to mercury is important due to its adverse health effects. This study aimed to determine the extent of mercury exposure among mothers and their children in Ireland, and to identify factors associated with elevated levels. It formed part of the Demonstration of a study to Coordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES) pilot biomonitoring study. Methods: Hair mercury concentrations were determined from a convenience sample of 120 mother/child pairs. Mothers also completed a questionnaire. Rigorous quality assurance within DEMOCOPHES guaranteed the accuracy and international comparability of results. Results: Mercury was detected in 79.2% of the samples from mothers, and 62.5% of children’s samples. Arithmetic mean levels in mothers (0.262 µg/g hair) and children (0.149 µg /g hair) did not exceed the US EPA guidance value. Levels were significantly higher for those with higher education, and those who consumed more fish. Conclusions: The study demonstrates the benefit of human biomonitoring for assessing and comparing internal exposure levels, both on a population and an individual basis. It enables the potential harmful impact of mercury to be minimised in those highly exposed, and can therefore significantly contribute to population health.