Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration

Protein misfolding caused by inherited mutations leads to loss of protein function and potentially toxic ‘gain of function’, such as the dominant P23H rhodopsin mutation that causes retinitis pigmentosa (RP). Here, we tested whether the AMPK activator metformin could affect the P23H rhodopsin synthesis and folding. In cell models, metformin treatment improved P23H rhodopsin folding and traffic. In animal models of P23H RP, metformin treatment successfully enhanced P23H traffic to the rod outer segment, but this led to reduced photoreceptor function and increased photoreceptor cell death. The metformin-rescued P23H rhodopsin was still intrinsically unstable and led to increased structural instability of the rod outer segments. These data suggest that improving the traffic of misfolding rhodopsin mutants is unlikely to be a practical therapy, because of their intrinsic instability and long half-life in the outer segment, but also highlights the potential of altering translation through AMPK to improve protein function in other protein misfolding diseases

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Photoreceptor replacement therapy:challenges presented by the diseased recipient retinal environment

AbstractVision loss caused by the death of photoreceptors is the leading cause of irreversible blindness in the developed world. Rapid advances in stem cell biology and techniques in cell transplantation have made photoreceptor replacement by transplantation a very plausible therapeutic strategy. These advances include the demonstration of restoration of vision following photoreceptor transplantation and the generation of transplantable populations of donor cells from stem cells. In this review, we present a brief overview of the recent progress in photoreceptor transplantation. We then consider in more detail some of the challenges presented by the degenerating retinal environment that must play host to these transplanted cells, how these may influence transplanted photoreceptor cell integration and survival, and some of the progress in developing strategies to circumnavigate these issues.</jats:p

Müller Glia Activation in Response to Inherited Retinal Degeneration Is Highly Varied and Disease-Specific

<div><p>Despite different aetiologies, most inherited retinal disorders culminate in photoreceptor loss, which induces concomitant changes in the neural retina, one of the most striking being reactive gliosis by Müller cells. It is typically assumed that photoreceptor loss leads to an upregulation of glial fibrilliary acidic protein (Gfap) and other intermediate filament proteins, together with other gliosis-related changes, including loss of integrity of the outer limiting membrane (OLM) and deposition of proteoglycans. However, this is based on a mix of both injury-induced and genetic causes of photoreceptor loss. There are very few longitudinal studies of gliosis in the retina and none comparing these changes across models over time. Here, we present a comprehensive spatiotemporal assessment of features of gliosis in the degenerating murine retina that involves Müller glia. Specifically, we assessed Gfap, vimentin and chondroitin sulphate proteoglycan (CSPG) levels and outer limiting membrane (OLM) integrity over time in four murine models of inherited photoreceptor degeneration that encompass a range of disease severities (<i>Crb1^rd8/rd8, Prph2^+/Δ307, Rho^-/-, Pde6b^rd1/rd1</i>). These features underwent very different changes, depending upon the disease-causing mutation, and that these changes are not correlated with disease severity. Intermediate filament expression did indeed increase with disease progression in <i>Crb1^rd8/rd8</i> and <i>Prph2^+/Δ307</i>, but decreased in the <i>Prph2^+/Δ307</i> and <i>Pde6b^rd1/rd1</i> models. CSPG deposition usually, but not always, followed the trends in intermediate filament expression. The OLM adherens junctions underwent significant remodelling in all models, but with differences in the composition of the resulting junctions; in <i>Rho^-/-</i> mice, the adherens junctions maintained the typical rod-Müller glia interactions, while in the <i>Pde6b^rd1/rd1</i> model they formed predominantly between Müller cells in late stage of degeneration. Together, these results show that gliosis and its associated processes are variable and disease-dependent.</p></div

Summary of the different models and stages of retinal degeneration studied.

<p>WT, wild-type.</p><p>^$ Wild-type is stationary.</p><p>* <i>Crb1</i>^{<i>rd8/rd8</i>} undergoes focal degeneration on this background, which broadly correlates with the stages outlined here.</p><p>Summary of the different models and stages of retinal degeneration studied.</p

OLM adherens junctions undergo significant remodelling during retinal degeneration in order to maintain OLM integrity.

<p><b>A</b>. In wild-type retinae, the OLM presented as a neat continuous line at the outer edge of the ONL, which remained unbroken throughout all the stages examined (i, iii). The majority of adherens junctions were formed between photoreceptor inner segments and Müller glia end feet (ii, iv). <b>B</b>. In the <i>Crb1</i>^{<i>rd8/rd8</i>} model, the OLM was discontinuous with photoreceptor cell bodies mislocalized in the segment region and/or subretinal space (arrows) (i, iii). Large regions of the outer margin of the ONL were devoid of adherens junctions (asterisks). <b>C</b>. In the <i>Prph2</i>^{<i>+/Δ307</i>} retina, there was moderate OLM disorganization and mislocalization of photoreceptor cell bodies at both early and late time points (i, iii). While junctions were aligned early on, there was reduction in number and organization of the junctions by the latest age examined (ii, iv). <b>D</b>. In early degeneration in the <i>Rho</i>^-/- model, there was some minor disorganization of the ONL, with occasional mislocalization of photoreceptor cell bodies (i, iii). Larger gaps between junctions were seen at late, compared with early, degeneration (ii, iv). <b>E</b>. In the <i>Pde6b</i>^{<i>rd1/rd1</i>} retina, both the ONL and the OLM became markedly disorganized (i, iii). Adherens junction alignment at the outer margin of the ONL was relatively normal at the earliest stage examined but was very disorganized by the latest stage (ii, iv). OLM integrity was assessed at early and late stage of retinal degeneration using semi-thin sections (100x; Scale bar, 25 μm.) and ultrathin electron microscopy (magnification 10,000x; Scale bar, 1 μm). Red boxes: adherens junctions; PR—photoreceptor; MG—Müller glia; arrows indicate displaced photoreceptors; ONL continuity—black dashed line marked on semi—thin sections.</p

OLM integrity, as assessed by adherens junction adaptor protein staining, is largely maintained during retinal degeneration.

<p><b>A</b> i-vi). In wild-type retinae, Zo-1 staining appeared as a continuous line, indicating that the OLM is intact, and remained so at all ages examined. <b>B</b>. i-vi) In <i>Crb1</i>^{<i>rd8/rd8</i>} animals, Zo-1 staining was noticeably fragmented at all time points examined, indicating significant OLM disruption. <b>C</b>. i-vi) In <i>Prph2</i>^{<i>+/Δ307</i>} animals model, the OLM was disrupted as indicated by fragmented Zo-1 staining. <b>D</b>. (i-vii) In <i>Rho</i>^-/- mice, no major changes within the OLM were observed at early and mid-stage of degeneration, but some fragmentation developed by late stage of degeneration. <b>E</b>. (i-vi) In <i>Pde6b</i>^{<i>rd1/rd1</i>} mice, staining for Zo-1 presented as a strong and continuous line at the earliest time point examined, P10, but became increasingly uneven with degeneration. Cryosections were immunostained for Zo-1 (red) and counterstained with nuclei marker Hoechst 33342 (blue). Scale bar, 25 μm. INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OLM, outer limiting membrane.</p