Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration

Abstract Misfolded alpha-synuclein (αSyn) is a major constituent of Lewy bodies and Lewy neurites, which are pathological hallmarks of Parkinson’s disease (PD). The contribution of αSyn to PD is well established, but the detailed mechanism remains obscure. Using a model in which αSyn aggregation in primary neurons was seeded by exogenously added, preformed αSyn amyloid fibrils (PFF), we found that a majority of pathogenic αSyn (indicated by serine 129 phosphorylated αSyn, ps-αSyn) was membrane-bound and associated with mitochondria. In contrast, only a minuscule amount of physiological αSyn was mitochondrial bound. In vitro, αSyn PFF displayed a stronger binding to purified mitochondria than did αSyn monomer, revealing a preferential mitochondria binding by aggregated αSyn. This selective mitochondrial ps-αSyn accumulation was confirmed in other neuronal and animal αSyn aggregation models that do not require exogenously added PFF and, more importantly, in postmortem brain tissues of patients suffering from PD and other neurodegenerative diseases with αSyn aggregation (α-synucleinopathies). We also showed that the mitochondrial ps-αSyn accumulation was accompanied by defects in cellular respiration in primary neurons, suggesting a link to mitochondrial dysfunction. Together, our results show that, contrary to physiological αSyn, pathogenic αSyn aggregates preferentially bind to mitochondria, indicating mitochondrial dysfunction as the common downstream mechanism for α-synucleinopathies. Our findings suggest a plausible model explaining the formation and the peculiar morphology of Lewy body and reveal that disrupting the interaction between ps-αSyn and the mitochondria is a therapeutic target for α-synucleinopathies.https://deepblue.lib.umich.edu/bitstream/2027.42/148288/1/40478_2019_Article_696.pd

Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits

Epidemiological studies suggest a link between type-2 diabetes and Parkinson’s disease (PD) risk. Treatment of type-2 diabetes with insulin sensitizing drugs lowers the risk of PD. We previously showed that the insulin sensitizing drug, MSDC-0160, ameliorates pathogenesis in some animal models of PD. MSDC-0160 reversibly binds the mitochondrial pyruvate carrier (MPC) protein complex, which has an anti-inflammatory effect and restores metabolic deficits. Since PD is characterized by the deposition of α-synuclein (αSyn), we hypothesized that inhibiting the MPC might directly inhibit αSyn aggregation in vivo in mammals. To answer if modulation of MPC can reduce the development of αSyn assemblies, and reduce neurodegeneration, we treated two chronic and progressive mouse models; a viral vector-based αSyn overexpressing model and a pre-formed fibril (PFF) αSyn seeding model with MSDC-0160. These two models present distinct types of αSyn pathology but lack inflammatory or autophagy deficits. Contrary to our hypothesis, we found that a modulation of MPC in these models did not reduce the accumulation of αSyn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of αSyn. These results are consistent with the lack of a direct effect of MPC modulation on synuclein clearance in these models

Determining the Phosphorus Release Curve for Smizyme TS G5 2,500 Phytase from 500 to 2,500 FTU/kg in Nursery Pig Diets

A total of 320 pigs (DNA 241 × 600; initially 26.2 ± 0.48 lb BW) were used in a 21-d growth study to determine the available P (aP) release curve for Smizyme TS G5 2,500 (Barentz, Woodbury, MN). At approximately 19 d of age, pigs were weaned, randomly allotted to pens, and fed common starter diets. Pigs were blocked by average pen body weight (BW) and randomly allotted to 1 of 8 dietary treatments on d 18 post-weaning, considered d 0 of the study. Dietary treatments were derived from a single basal diet and ingredients including phytase, monocalcium P, limestone, and sand were added to create the treatment diets. Treatments included 3 diets containing increasing (0.11, 0.19, and 0.27%) inorganic P from monocalcium P, or 5 diets with increasing phytase (500, 1,000, 1,500, 2,000, or 2,500 FTU/kg) added to the diet containing 0.11% aP. All diets were corn-soybean meal-canola meal-based and were formulated to contain 1.24% SID Lys and an analyzed Ca:P ratio of 1.10:1. Prior to the beginning of the study, all pigs were fed a diet containing 0.11% aP for a 2-d period (d 16 to 18 post-weaning). At the conclusion of the study, 1 pig, closest to the mean weight of each pen, was euthanized and the right fibula, rib, and metacarpal were collected to determine bone ash, density, and total bone P. For the overall experimental period, pigs fed increasing inorganic P had improved (quadratic, P ≤ 0.053) ADG, ADFI, F/G, and final BW. Pigs fed increasing phytase had improved (quadratic, P ≤ 0.004) ADG, F/G, and final BW and increased (linear, P = 0.019) ADFI. For fibula, rib, and metacarpal characteristics, pigs fed increasing levels of aP from inorganic P had increased (linear, P \u3c 0.001) bone ash weight, bone ash percentage, bone density, and bone P. Additionally, pigs fed increasing phytase had increased (P \u3c 0.05) bone ash weight, bone ash percentage, bone density, and bone P in either a linear or quadratic manner depending upon bone. The available P release curve generated for Smizyme TS G5 2,500 for percentage bone ash is: aP = (0.219 × FTU) ÷ (993.238 + FTU)

Evaluating the Effects of Increasing Sodium Diformate on Nursery Pig Growth Performance and Fecal Dry Matter

A total of 360 weanling barrows (DNA 200 × 400, DNA; initially 13.1 ± 0.12 lb) were used in a 38-d growth trial to evaluate the effects of dietary sodium diformate on nursery pig growth performance and fecal dry matter. At weaning, pigs were randomly assigned to pens with five pigs per pen and 12 pens per treatment. There were six dietary treatments formulated to provided none, 0.40, 0.60, 0.80, 1.00, and 1.20% sodium diformate (Formi NDF, ADDCON, Nordic AS, Porsgrunn, Norway) added at the expense of corn. Experimental diets were fed in three phases: phase 1 from weaning to d 9, phase 2 from d 9 to 24, and phase 3 from d 24 to 38. From d 0 to 24 (phases 1 and 2), increasing sodium diformate improved (linear, P = 0.001) F/G. However, sodium diformate did not affect (P \u3e 0.10) ADG or ADFI. From d 24 to 38 (phase 3) and overall (d 0 to 38), there was no evidence of differences (P \u3e 0.10) in any of the growth performance criteria. There was no evidence for differences (P \u3e 0.10) in fecal DM on d 9. However, fecal DM decreased (linear, P \u3c 0.05) as sodium diformate increased on d 24 with pigs fed 0.40% sodium diformate having the highest percentage fecal DM. Additionally, there was evidence for a main effect of day (P \u3c 0.001) with fecal DM being lower on d 24 compared to d 9. In conclusion, these data suggest increasing sodium diformate has the potential to improve feed efficiency in the early nursery period but did not affect performance in the late nursery

Loss of One Engrailed1 Allele Enhances Induced α-Synucleinopathy

Parkinson’s disease (PD) is a synucleinopathy that has multiple neuropathological characteristics, with nigrostriatal dopamine system degeneration being a core feature. Current models of PD pathology typically fail to recapitulate several attributes of the pathogenic process and neuropathology. We aimed to define the effects of combining a mouse model exhibiting multiple PD-like changes with intrastriatal injections of α-synuclein (α-syn) pre-formed fibril (PFFs) aggregates. We employed the heterozygous Engrailed 1 (En1+/–) mouse that features several pathophysiological hallmarks of clinical PD.La enfermedad de Parkinson (EP) es una sinucleinopatía que tiene múltiples características neuropatológicas, siendo la degeneración del sistema dopaminérgico nigroestriatal una característica central. Los modelos actuales de patología de la EP generalmente no logran recapitular varios atributos del proceso patogénico y la neuropatología. Nuestro objetivo fue definir los efectos de combinar un modelo de ratón que presentaba múltiples cambios similares a los de la EP con inyecciones intraestriatales de agregados de fibrillas preformadas (PFF) de α-sinucleína (α-syn). Empleamos el ratón heterocigoto Engrailed 1 (En1+/–) que presenta varias características fisiopatológicas de la EP clínica

High-throughput low-cost nl-qPCR for enteropathogen detection: A proof-of-concept among hospitalized patients in Bangladesh.

BACKGROUND: Diarrheal disease is a leading cause of morbidity and mortality globally, especially in low- and middle-income countries. High-throughput and low-cost approaches to identify etiologic agents are needed to guide public health mitigation. Nanoliter-qPCR (nl-qPCR) is an attractive alternative to more expensive methods yet is nascent in application and without a proof-of-concept among hospitalized patients. METHODS: A census-based study was conducted among diarrheal patients admitted at two government hospitals in rural Bangladesh during a diarrheal outbreak period. DNA was extracted from stool samples and assayed by nl-qPCR for common bacterial, protozoan, and helminth enteropathogens as the primary outcome. RESULTS: A total of 961 patients were enrolled; stool samples were collected from 827 patients. Enteropathogens were detected in 69% of patient samples; More than one enteropathogen was detected in 32%. Enteropathogens most commonly detected were enteroaggregative Escherichia coli (26.0%), Shiga toxin-producing E.coli (18.3%), enterotoxigenic E. coli (15.5% heat stable toxin positive, 2.2% heat labile toxin positive), Shigella spp. (14.8%), and Vibrio cholerae (9.0%). Geospatial analysis revealed that the median number of pathogens per patient and the proportion of cases presenting with severe dehydration were greatest amongst patients residing closest to the study hospitals." CONCLUSIONS: This study demonstrates a proof-of-concept for nl-qPCR as a high-throughput low-cost method for enteropathogen detection among hospitalized patients

Germinal center B cells recognize antigen through a specialized immune synapse architecture

B cell activation is regulated by B cell antigen receptor (BCR) signaling and antigen internalization in immune synapses. Using large-scale imaging across B cell subsets, we show that in contrast to naive and memory B cells, which gathered antigen towards the synapse center before internalization, germinal center (GC) B cells extracted antigen by a distinct pathway using small peripheral clusters. Both naive and GC B cell synapses required proximal BCR signaling, but GC cells signaled less through the protein kinase C-β (PKC-β)–NF-κB pathway and produced stronger tugging forces on the BCR, thereby more stringently regulating antigen binding. Consequently, GC B cells extracted antigen with better affinity discrimination than naive B cells, suggesting that specialized biomechanical patterns in B cell synapses regulate T-cell dependent selection of high-affinity B cells in GCs

Society of Behavioral Medicine position statement: early care and education (ECE) policies can impact obesity prevention among preschool-aged children

The Society of Behavioral Medicine (SBM) urges policymakers to help prevent childhood obesity by improving state regulations for early care and education (ECE) settings related to child nutrition, physical activity, and screen time. More than three quarters of preschool-aged children in the USA attend ECE settings, and many spend up to 40 h per week under ECE care. ECE settings provide meals and snacks, as well as opportunities for increasing daily physical activity and reducing sedentary screen time. However, many states\u27 current policies do not adequately address these important elements of obesity prevention. A growing number of cities and states, child health organizations, medical and early childhood associations, and academic researchers are beginning to identify specific elements of policy and regulations that could transform ECE settings into environments that contribute to obesity prevention. Let\u27s Move! Child Care recommends a set of straightforward regulations addressing nutrition, physical activity, and screen time in ECE settings. These emerging models provide local and state leaders with concrete steps to implement obesity prevention initiatives. We provide a set of recommendations based upon these models that will help state and local policymakers to improve current policies in ECE settings

Impacts of COVID-19 quarantine and isolation on adolescent social functioning

This review discusses research conducted globally between March 2020 and March 2023 examining the impact of the COVID-19 pandemic on adolescent social functioning, including their lifestyle, extracurricular activities, family environment, peer environment, and social skills. Research highlights the widespread impact, with largely negative effects. However, a handful of studies support improved quality of relationships for some young people. Study findings underscore the importance of technology for fostering social communication and connectedness during periods of isolation and quarantine. Most studies specifically examining social skills were cross-sectional and conducted in clinical populations, such as autistic or socially anxious youth. As such, it is critical that ongoing research examines the long-term social impacts of the COVID-19 pandemic, and ways to promote meaningful social connectedness via virtual interactions