LRRK2 Parkinson disease mutations enhance its microtubule association.

Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic causes of Parkinson disease (PD) and genome-wide association studies identify LRRK2 sequence variants as risk factors for sporadic PD. Intact kinase function appears critical for the toxicity of LRRK2 PD mutants, yet our understanding of how LRRK2 causes neurodegeneration remains limited. We find that most LRRK2 PD mutants abnormally enhance LRRK2 oligomerization, causing it to form filamentous structures in transfections of cell lines or primary neuronal cultures. Strikingly, ultrastructural analyses, including immuno-electron microscopy and electron microscopic tomography, demonstrate that these filaments consist of LRRK2 recruited onto part of the cellular microtubule network in a well-ordered, periodic fashion. Like LRRK2-related neurodegeneration, microtubule association requires intact kinase function and the WD40 domain, potentially linking microtubule binding and neurodegeneration. Our observations identify a novel effect of LRRK2 PD mutations and highlight a potential role for microtubules in the pathogenesis of LRRK2-related neurodegeneration.

Emotional responses and psychological health among young people amid climate change, Fukushima's radioactive water release, and wars in Ukraine and the Middle East, and the mediating roles of media exposure and nature connectedness: a cross-national analysis.

BACKGROUND: New global crises are emerging, while existing global crises remain unabated. Coping with climate change, the radioactive water released into the Pacific Ocean subsequent to the Fukushima nuclear accident in Japan, and the wars in Ukraine and the Middle East (hereafter referred to as the wars) as individual crises can negatively affect the psychological health of young people, but little is known about the compounded impact of multiple crises. We aimed to examine: (1) the emotional responses of young people towards each individual crisis, (2) how aggregate levels of emotional engagement in global crises might pose different potential trajectories in psychological health, and (3) the protective or exacerbating role of media exposure and nature connectedness as mediators on psychological health outcomes of young people. METHODS: We conducted a cross-national online survey among young people (aged 18-29 years) from China, Portugal, South Africa, the USA, and the UK. We adopted stratified purposive sampling and distributed the survey using online platforms (www.wenjuan.com and www.prolific.com). Individuals were eligible for inclusion in our analysis if they were literate in Chinese or English and had no mental disorders diagnosed within the past 12 months. Participants were asked questions on their demographic characteristics and time spent on social media, including proportion of time exposed to media pertaining to global crises of interest, and they completed surveys based on validated scales that measure depression, anxiety, stress, and wellbeing, as well as emotional responses to each global crisis and nature relatedness. We assessed the survey results using descriptive statistics, ANOVA tests, cluster analysis for individual emotional responses, and structural equation modelling for the aggregate measure of emotional engagement towards individual global crises. FINDINGS: Between Oct 20 and Nov 3, 2023, 2579 individuals participated in the survey, of whom 400 participants from each country (200 male and 200 female participants) were included in our analysis (mean age 24·36 years [SD 2·86]). The mean emotional engagement varied between the global crises of interest (on a scale from 0 to 68, where 0 indicates no emotional response and 68 indicates strong emotional responses across 17 different emotions; wars: 32·42 [SD 14·57]; climate change: 28·79 [14·17]; radioactive water: 21·26 [16·08]), and emotional engagement also varied by country; for instance, for respondents from China, mean emotional engagement in radioactive water was relatively high (39·15 [10·72]) compared with the other countries, and for respondents from the USA, engagement with the wars was relatively low (29·45 [15·78]). We found significant variations in the level of emotional engagement between different crises, with distinct emotional profiles observed among individual countries. To assess the role of media exposure and nature connectedness on psychological outcomes, using structural equation modelling, we constructed a multi-country model comprising Portugal, South Africa, the USA, and the UK, and a standalone model for China. These models elucidated associations between emotional engagement and psychological distress and wellbeing, explaining substantial portions of the variance in both. Notably, while greater emotional engagement in the ecological crises (ie, climate change and radioactive water) generally predicted worse psychological health outcomes, we found the direction of effect for war crises to have positive outcomes for mental health in the standalone China model. Additionally, we found that media exposure mediated the negative effect of wars on psychological distress in the multi-country model, and positive psychological wellbeing in the standalone China model. Moreover, nature connectedness emerged as a potent mediator, effectively mitigating the adverse mental health effects of emotional engagement with some crises, such as radioactive water and climate change. INTERPRETATION: Our findings offer valuable insights into the nuanced dynamics of emotional engagement in global crises and its implications for mental health outcomes among young people across diverse global contexts. Further research is needed to understand the contribution of ongoing and new global crises towards a compounded negative future outlook on young people's mental health to identify effective communication and intervention strategies that can mitigate the effect of this global challenge. FUNDING: Research Grants Council of Hong Kong, China.

Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial (PRISM-RCT) in Chinese patients with young-onset diabetes: design, methods and baseline characteristics.

INTRODUCTION: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines. RESEARCH DESIGN AND METHODS: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications. RESULTS: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes. CONCLUSIONS: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events. TRIAL REGISTRATION NUMBER: NCT04049149.

Literature review and development of pictorial action plan to promote self-management of chronic obstructive pulmonary disease.

OBJECTIVE: This study aimed to review relevant literature and develop a pictorial action plan (PAP) to enhance self-management among older patients with chronic obstructive pulmonary disease (COPD). METHODS: In Stage 1, an integrative review was conducted to identify key elements of respiratory self-management action plans. In Stage 2, cartoon pictograms with plain descriptions were designed. In Stage 3, the PAP was validated by 40 older patients with COPD and an expert panel. RESULTS: While the eight included studies demonstrated positive effects on knowledge and quality of life, key elements identified included: traffic light motif, plain and explicit language, and several action plan topics. The final PAP comprises three traffic light-coloured zones and 24 pictograms that introduce self-management strategies for normal, decreasing, and severely decreased airflow. After revising the cartoon characters, all of the pictograms received guessability ratings above 70% and acceptable mean translucency ratings. DISCUSSION: The integrative review provides evidence about the effectiveness and key elements of PAPs. The PAP developed was found to be valid and feasible for use among older patients with chronic respiratory conditions. PRACTICE IMPLICATIONS: This study offered an example of translating evidence into patient education practice to enhance self-management in older patients with COPD.

Measurement of burnout during the prolonged pandemic in the Chinese zero-COVID context: COVID-19 burnout views scale.

Burnout is an important public health issue at times of the COVID-19 pandemic. Current measures which focus on work-based burnout have limitations in length and/or relevance. When stepping into the post-pandemic as a new Norm Era, the burnout scale for the general population is urgently needed to fill the gap. This study aimed to develop a COVID-19 Burnout Views Scale (COVID-19 BVS) to measure burnout views of the general public in a Chinese context and examine its psychometric properties. A multiphase approach including literature review, expert consultation, and pilot testing was adopted in developing the scale. The scale was administered to a sample of 1,078 of the general public in Hong Kong with an average age of 34.45 years (SD = 12.47). Exploratory and Confirmatory Factor Analyses suggested a 5-item unidimensional model of COVID-19 BVS. The CFA results indicated that the COVID-19 BVS had a good model fit, as χ2 (10.054)/5 = 2.01, SRMR = 0.010, CFI = 0.998, RMSEA = 0.031. Five items were maintained in EFA with high internal consistency in terms of Cronbach's α of 0.845 and McDonald's ω coefficient of 0.87, and the corrected item-to-total correlations of 0.512 to 0.789 are way above the acceptable range. The KMO values of 0.841 and Bartlett's Test of Sphericity (p < 0.01) verified the normal distribution of the EFA and the adequacy of the EFA sampling. The analyses suggest that the COVID-19 BVS is a promising tool for assessing burnout views on the impacts of the epidemic on the Chinese general populations.

Targeted disruption of neuronal 19S proteasome subunits induces the formation of ubiquitinated inclusions in the absence of cell death.

Proteasome-mediated proteolysis is a major protein degradation mechanism in cells and its dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, each with the common features of neuronal death and formation of ubiquitinated inclusions found within neurites, the cell body, or nucleus. Previous models of proteasome dysfunction have employed pharmacological inhibition of the catalytic subunits of the 20S proteasome core, or the genetic manipulation of specific subunits resulting in altered proteasome assembly. In this study, we report the use of dominant negative subunits of the 19S regulatory proteasome complex that mediate the recognition of ubiquitinated substrates as well as the removal of the poly-ubiquitin chain. Interestingly, while each mutant subunit-induced inclusion formation, like that seen with pharmacological inhibition of the 20S proteasome, none was able to induce apoptotic death, or trigger activation of macroautophagy, in either dopaminergic cell lines or primary cortical neurons. This finding highlights the dissociation between the mechanisms of neuronal inclusion formation and the induction of cell death, and represents a novel cellular model for Lewy body-like inclusion formation in neurons.

Implantation and long-term assessment of the stability and biocompatibility of a novel 98 channel suprachoroidal visual prosthesis in sheep.

Severe visual impairment can result from retinal degenerative diseases such as retinitis pigmentosa, which lead to photoreceptor cell death. These pathologies result in extensive neural and glial remodelling, with survival of excitable retinal neurons that can be electrically stimulated to elicit visual percepts and restore a form of useful vision. The Phoenix99 Bionic Eye is a fully implantable visual prosthesis, designed to stimulate the retina from the suprachoroidal space. In the current study, nine passive devices were implanted in an ovine model from two days to three months. The impact of the intervention and implant stability were assessed using indirect ophthalmoscopy, infrared imaging, and optical coherence tomography to establish the safety profile of the surgery and the device. The biocompatibility of the device was evaluated using histopathological analysis of the tissue surrounding the electrode array, with a focus on the health of the retinal cells required to convey signals to the brain. Appropriate stability of the electrode array was demonstrated, and histological analysis shows that the fibrotic and inflammatory response to the array was mild. Promising evidence of the safety and potential of the Phoenix99 Bionic Eye to restore a sense of vision to the severely visually impaired was obtained.

Safety and biocompatibility of a bionic eye: Imaging, intraocular pressure, and histology data.

The data presented here are related and supplementary data to the research article "Implantation and long-term assessment of the stability and biocompatibility of a novel 98 channel suprachoroidal visual prosthesis in sheep" [1]. In Eggenberger et al., nine sheep of the Suffolk (N=2) and Dorper (N=7) breeds were implanted in the left eye with an electrically inactive, suprachoroidal retinal stimulator (Bionic Eye) for durations of up to 100 days. The surgical safety, implant stability and device biocompatibility were assessed. Intraocular pressure measurements, indirect and infrared ophthalmoscopy and optical coherence tomography were performed at fixed time points to evaluate the clinical effects of the surgery and device implantation. Post-mortem eye tissue collection and histology was performed to measure the effects of the intervention at the cellular level. The data, including a comprehensive collection of fundus, infrared, optical coherence tomography and histology images can be used as a reference for comparison with other research, for example, active retinal stimulators. Furthermore, these data can be used to evaluate the suitability of the sheep model, in particular Dorper sheep, for future research.

The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration.

Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD), but the mechanisms by which mutant forms of LRRK2 disrupt neuronal function and cause cell death remain poorly understood. We report that LRRK2 interacts with the death adaptor Fas-associated protein with death domain (FADD), and that in primary neuronal culture LRRK2-mediated neurodegeneration is prevented by the functional inhibition of FADD or depletion of caspase-8, two key elements of the extrinsic cell death pathway. This pathway is activated by disease-triggering mutations, which enhance the LRRK2-FADD association and the consequent recruitment and activation of caspase-8. These results establish a direct molecular link between a mutant PD gene and the activation of programmed cell death signaling, and suggest that FADD/caspase-8 signaling contributes to LRRK2-induced neuronal death.

The biology and pathology of the familial Parkinson's disease protein LRRK2.

Parkinson's disease (PD) is typically a sporadic illness, but the past decade has witnessed the identification of mutations responsible for multiple familial forms of the disease. The proposed functions of some of these genes (e.g., E3 ubiquitin ligase, redox-dependent chaperone) have led to the hypothesis that dysfunction of protein quality control pathways contributes to PD neurodegeneration. However, the key signaling events that act downstream of misfolded proteins to cause cell death remain poorly defined. The discovery of the familial PD kinase leucine-rich repeat kinase 2 (LRRK2) holds great promise for the elucidation of signaling events relevant to PD neurodegeneration. This review will summarize current knowledge of the clinical and cell biological features of LRRK2, the most common inherited cause of Parkinsonism.

Effects of the monoacylglycerol lipase inhibitor JZL184 on chickens infected with avian pathogenic Escherichia coli O78: A preliminary pharmacokinetic and infection study.

The endocannabinoid (eCB) system modulates the degree of injury caused by inflammation, while enhancing the activity of phagocytes that promote resolution of inflammation and tissue repair. In-vitro studies with the monoacylglycerol lipase (MAGL) inhibitor JZL184 have suggested that increased eCB signaling might enhance the ability of the host immune system to clear invading pathogens. Although the neurochemical effects of JZL184 on the eCB system in rodents are well-known, its immuneregulating effects are less clear, especially in chickens. The primary objective of this study was to explore whether modulating the eCB system affects immune responses in chickens. To do this, we administered JZL184 [10 and 40 mg/kg body weight (BW), intraperitoneal injection] into chickens prior to a challenge with avian pathogenic Escherichia coli (APEC) O78. Bacteria were isolated from livers, blood, air sacs, and hearts at 8, 28, and 56 h post-infection and the gross lesions in air sacs, livers, and hearts were also examined. Serum levels of JZL184 were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which indicated that the drug was distributed systemically. The number of birds positive for airsacculitis after APEC O78 challenge was marginally higher in groups treated with JZL184 than in the control group (P = 0.064). Rather than augmenting host defense and enhancing pathogen clearance, these results suggested that JZL184 might have immunosuppressive effects that exacerbated APEC O78 infection in chickens.

Le système de l'endocannabinoïde (eCB) module le degré de blessure causé par une inflammation, tout en augmentant l'activité des phagocytes qui favorise la résolution de l'inflammation et la réparation tissulaire. Des études in vitro avec l'inhibiteur de la monoacylglycérol lipase (MAGL) JZL184 suggèrent qu'une augmentation du signal d'eCB pourrait augmenter la capacité du système immunitaire de l'hôte à éliminer les agents pathogènes envahisseurs. Bien que les effets neurochimiques du JZL184 sur le système eCB des rongeurs est bien connu, ses effets immuno-régulateurs sont moins clairs, spécialement chez les poulets. L'objectif primaire de la présente étude était d'explorer si une modulation du système eCB affecte les réponses immunitaires des poulets. Pour se faire, nous avons administré JZL184 [10 et 40 mg/kg de poids corporel (BW), par injection intrapéritonéale] à des poulets avant une infection défi avec l'agent pathogène aviaire Escherichia coli (APEC) O78. Des bactéries furent isolées du foie, du sang, des sacs aériens et du coeur à 8, 28 et 56 h post-infection et les lésions macroscopiques dans les sacs aériens, le foie et le coeur furent également examinées. Les niveaux sériques de JZL184 furent quantifiés par chromatographie liquide couplée à la spectrométrie de masse en tandem (LC-MS/MS), qui indiqua que le médicament était distribué systémiquement. Le nombre d'oiseaux positifs pour aérosacculite après infection par APEC O78 était légèrement plus élevé dans le groupe traité avec JZL184 que dans le groupe témoin (P = 0,064). Plutôt que d'augmenter les mécanismes de défense de l'hôte et d'améliorer l'élimination de l'agent pathogène, ces résultats suggèrent que JZL184 pourrait avoir des effets immunosuppresseurs qui ont exacerbé l'infection par APEC O78 chez les poulets.(Traduit par Docteur Serge Messier).

Multiple primary intramedullary ependymomas: a case report and review of the literature.

BACKGROUND CONTEXT: Intramedullary ependymomas constitute the most frequent type of intramedullary tumor. In patients with neurofibromatosis type 2 (NF2), multiple intramedullary ependymomas are known to occur. In the non-NF2 population, however, the presence of multiple synchronous intramedullary ependymomas is exceedingly rare. PURPOSE: In this article, the authors report the second case in the literature of multiple primary synchronous intramedullary ependymomas. To the best of the authors knowledge, this report represents the first to provide a detailed pathology of all lesions, thereby giving an added level of confidence on the primary synchronous nature of the lesions. The authors have also performed a review of the literature regarding multifocal intramedullary ependymomas. STUDY DESIGN: A review article and case report. CONCLUSIONS: The concomitant localization of two primary intramedullary spinal cord ependymomas in the setting of nongenetic predisposition is an uncommon phenomenon. In this article, the authors present the second report of multiple, synchronous intramedullary ependymomas. A detailed review of the literature reveals that the presence of multiple intramedullary lesions in non-NF2 patients is both rare and deserving of further study.

The WD40 domain is required for LRRK2 neurotoxicity.

BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD). LRRK2 contains an "enzymatic core" composed of GTPase and kinase domains that is flanked by leucine-rich repeat (LRR) and WD40 protein-protein interaction domains. While kinase activity and GTP-binding have both been implicated in LRRK2 neurotoxicity, the potential role of other LRRK2 domains has not been as extensively explored. PRINCIPAL FINDINGS: We demonstrate that LRRK2 normally exists in a dimeric complex, and that removing the WD40 domain prevents complex formation and autophosphorylation. Moreover, loss of the WD40 domain completely blocks the neurotoxicity of multiple LRRK2 PD mutations. CONCLUSION: These findings suggest that LRRK2 dimerization and autophosphorylation may be required for the neurotoxicity of LRRK2 PD mutations and highlight a potential role for the WD40 domain in the mechanism of LRRK2-mediated cell death.