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A persistent accumulation of damaged mitochondria is part of prion disease pathogenesis. Normally, damaged mitochondria are cleared via a major pathway that involves the E3 ubiquitin ligase parkin and PTEN-induced kinase 1 (PINK1) that together initiate mitophagy, recognize and eliminate damaged mitochondria. However, the precise mechanisms underlying mitophagy in prion disease remain largely unknown. Using prion disease cell models, we observed PINK1-parkin-mediated mitophagy deficiency in which parkin depletion aggravated blocked mitochondrial colocalization with LC3-II-labeled autophagosomes, and significantly increased mitochondrial protein levels, which led to inhibited mitophagy. Parkin overexpression directly induced LC3-II colocalization with mitochondria and alleviated defective mitophagy. Moreover, parkin-mediated mitophagy was dependent on PINK1, since PINK1 depletion blocked mitochondrial Parkin recruitment and reduced optineurin and LC3-II proteins levels, thus inhibiting mitophagy. PINK1 overexpression induced parkin recruitment to the mitochondria, which then stimulated mitophagy. In addition, overexpressed parkin and PINK1 also protected neurons from apoptosis. Furthermore, we found that supplementation with two mitophagy-inducing agents, nicotinamide mononucleotide (NMN) and urolithin A (UA), significantly stimulated PINK1-parkin-mediated mitophagy. However, compared with NMN, UA could not alleviate prion-induced mitochondrial fragmentation and dysfunction, and neuronal apoptosis. These findings show that PINK1-parkin-mediated mitophagy defects lead to an accumulation of damaged mitochondria, thus suggesting that interventions that stimulate mitophagy may be potential therapeutic targets for prion diseases.

Prion diseases caused by the cellular prion protein (PrP C ) conversion into a misfolded isoform (PrP Sc ) are associated with multiple mitochondrial damages. We previously reported mitochondrial dynamic abnormalities and cell death in prion diseases via modulation of a variety of factors. Optic atrophy 1 (OPA1) is one of the factors that control mitochondrial fusion, mitochondrial DNA (mtDNA) maintenance, bioenergetics, and cristae integrity. In this study, we observed downregulation of OPA1 in prion disease models in vitro and in vivo, mitochondria structure damage and dysfunction, loss of mtDNA, and neuronal apoptosis. Similar mitochondria findings were seen in OPA1-silenced un-infected primary neurons. Overexpression of OPA1 not only alleviated prion-induced mitochondrial network fragmentation and mtDNA loss, decrease in intracellular ATP, increase in ADP/ATP ratio, and decrease in mitochondrial membrane potential but also protected neurons from apoptosis by suppressing the release of cytochrome c from mitochondria to cytosol and activation of the apoptotic factor, caspase 3. Our results demonstrated that overexpression of OPA1 alleviates prion-associated mitochondrial network fragmentation and cristae remodeling, mitochondrial dysfunction, mtDNA depletion, and neuronal apoptosis, suggesting that OPA1 may be a novel and effective therapeutic target for prion diseases.

Prion diseases are neurodegenerative disorders characterized by the accumulation of misfolded prion protein, spongiform changes in the brain, and brain inflammation as a result of the wide-spread activation of microglia. Autophagy is a highly conserved catabolic process for the clearance of cytoplasmic components, including protein aggregates and damaged organelles; this process also eliminates pathological PrP as it accumulates during prion infection. The NALP3 inflammasome is a multiprotein complex that is a component of the innate immune system and is responsible for the release of pro-inflammatory cytokines. Our previous study showed that the neurotoxic prion peptide PrP106-126 induces NALP3 inflammasome activation and subsequent IL-1β release in microglia. Autophagy is involved in the regulation of the immune responses and inflammation in many diseases including neurodegenerative diseases. However, the relationship between autophagy and NALP3 inflammasome in prion diseases has not been investigated. In this study, we demonstrated that the processing and release of mature IL-1β is significantly enhanced by the inhibition of autophagy. Conversely, gene-silencing of the NALP3 inflammasome promotes autophagy. Suppression of TRIF or TLR4 by siRNA attenuated PrP106-126-induced autophagy, which is indicating that the TLR4-TRIF signaling pathway is involved in PrP106-26-induced autophagy. Caspase 1 directly cleaved TRIF to diminish TLR-4-TRIF mediated autophagy. Our findings suggest that the inhibition of autophagy by NALP3 inflammasome is probably mediated by activated Caspase-1-induced TRIF cleavage. This is the first study reporting that the NALP3 inflammasome complex negatively regulates autophagy in response to PrP106-126 stimulation in microglia, and partly explains the mechanism of autophagy inhibition by Caspase-1 in PrP106-126-induced BV2 cell activation. Our findings suggest that autophagy up-regulation and inhibition of Caspase-1 may protect against prion-induced neuroinflammation and accelerate misfolded protein degradation and are potential therapeutic approaches for prion diseases.

The Editor-in-Chief has retracted this article [1] because of significant concerns regarding a number of figures presented in this work, which question the integrity of the data.

Background Species of the genus Eimeria cause coccidiosis in chickens, resulting in a huge burden to the poultry industry worldwide. Eimeria tenella is one of the most prevalent chicken coccidia in China, and E. tenella infection causes hemorrhagic cecitis. Methods Using an established model of coccidiosis in chickens combined with necropsy, imaging of pathological tissue sections, and other techniques, we evaluated the gross and microscopic lesions of cecal tissue within 15 days after inoculation with sporulated oocysts and described the endogenetic developmental process and relationship between E. tenella infection and enteritis development in chickens. Results We observed three generations of merogony and gamogony in E. tenella. We observed gross lesions in the cecum from 84 hpi (hours post inoculation) and microscopic lesions from 60 hpi. The lesions in the cecum mainly exhibited hemorrhagic enteritis. Their severity increased with the onset of the second generation of merogony. The lesions began to alleviate by the end of the endogenous stages of E. tenella. Conclusion We show, for the first time, the complete observation of a series of changes in enteritis caused by 5 × 103 E. tenella oocysts. This study provides reference materials for E. tenella research and pathological diagnosis. This study used necropsy, pathological tissue sections, and other techniques to evaluate the gross and microscopic lesions of cecal tissue in multiple periods within 15 days after incubation of sporulated oocysts. A model of necrotizing enteritis in chicken was developed by sporulated Eimeria tenella oocyst (5 × 103) infection. We observed in detail the process of merogony and sexual development in three generations of E. tenella, as well as the macroscopic lesions and histopathologic changes in the cecum that corresponded to their appearance.

Background. Whether elevated triglyceride (TG) levels during pregnancy were a biomarker for postpartum abnormal glucose metabolism (AGM) in women with previous gestational diabetes mellitus (GDM) remained unknown. The aim of this study was to investigate the association between TG levels during the second trimester and postpartum AGM in GDM women. Methods. This was a retrospective cohort study including 513 GDM women. A 75 g oral glucose tolerance test (OGTT) was performed, and lipid levels were determined during pregnancy and the postpartum period. GDM patients were categorized into tertiles according to their TG levels at 24–28 weeks of gestation (TG<2.14 mmol/L, TG: 2.14–2.89 mmol/L, and TG>2.89 mmol/L). A logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). Results. During pregnancy, women in the high TG tertile showed higher HbA1c levels (5.47±0.58% versus 5.28±0.49%, p=0.006), higher total cholesterol (TC) levels (5.85±1.23 mmol/L versus 5.15±0.97 mmol/L, p=0.026), and higher HOMA-IR (2.36 (1.62-3.45) versus 1.49 (0.97-2.33), p<0.001) than the participants in the low TG tertile. After delivery, the prevalence rates of AGM based on above tertiles of TG levels during pregnancy were 26.90%, 33.33%, and 43.27%, respectively (p=0.006). High TG tertile during the second trimester was associated with the presence of postpartum AGM (adjusted OR: 2.001, 95% CI: 1.054-3.800, p=0.034). Conclusions. The elevated midtrimester TG levels were not only accompanied by higher glucose and lipid levels and more severe insulin resistance at the time of the measurement but were a biomarker for postpartum AGM as well.

摘要 背景 前瞻性探索在中国的一个真实世界糖尿病中心中, 深度学习算法 (DLA) 在按糖尿病类型、血压、性别、BMI、年龄、HbA1c、糖尿病病程、肾小球滤过率(UACR)和估计肾小球滤过率(eGFR)水平分层的不同亚组中检测可参考糖尿病视网膜病变 (DR) 的临床价值。 方法 从 2018 年 10 月至 2019 年 8 月, 招募1147 名糖尿病患者。视网膜眼底图像由 DLA进行分级, 并将可参考 DR(中度非增殖性 DR 或更差)的检测与一位经认证拥有十二年以上经验的眼科专家的参考标准进行比较。评估按糖尿病类型、血压、性别、BMI、年龄、HbA1c、糖尿病病程、尿白蛋白与肌酐比和肾小球滤过率分层的不同亚组 DLA 的表现。 结果 对于所有 1674 个可分级图像, DLA 对可参考 DR 的 AUC、敏感度和特异度分别为 0.942(95% CI, 0.920‐0.964)、85.1%(95% CI, 83.4%‐86.8%)和 95.6% (95% CI, 94.6%96.6%)。 DLA 在大多数亚组中有一致的表现, 而在1型糖尿病、UACR≥30 mg/g和eGFR <90mL/min/1.73m2 的患者亚组中有优异的表现。 结论 本研究表明, DLA是检测可参考DR的一种可靠的替代方法, 并且在易发生DR的1型糖尿病和糖尿病肾病患者中表现更好。

Prion infections of the central nervous system (CNS) are characterized by initial reactive gliosis followed by overt neuronal death. Gliosis is likely to be caused initially by the deposition of misfolded, proteinase K-resistant, isoforms (termed PrPSc) of the normal cellular prion protein (PrPc) in the brain. Proinflammatory cytokines and chemokines released by PrPSc-activated glia and stressed neurons may also contribute directly or indirectly to the disease development by enhancing gliosis and inducing neurotoxicity. Recent studies have illustrated that early neuroinflammation activates nuclear factor of activated T cells (NFAT) in the calcineurin signaling cascade, resulting in nuclear translocation of nuclear factor kappa B (NF-κB) to promote apoptosis. Hence, useful therapeutic approaches to slow down the course of prion disease development should control early inflammatory responses to suppress NFAT signaling. Here we used a hamster model of prion diseases to test, for the first time, the neuroprotective and NFAT-suppressive effect of a second-generation semisynthetic tetracycline derivative, minocycline, versus a calcineurin inhibitor, FK506, with known NFAT suppressive activity. Our results indicate that prolonged treatment with minocycline, starting from the presymptomatic stage of prion disease was more effective than FK506 given either during the presymptomatic or symptomatic stage of prion disease. Specifically, minocycline treatment reduced the expression of the astrocyte activation marker glial fibrillary acidic protein and of the microglial activation marker ionized calcium-binding adapter molecule-1, subsequently reducing the level of proinflammatory cytokines interleukin 1β and tumor necrosis factor-α. We further found that minocycline and FK506 treatment inhibited mitogen-activated protein kinase p38 phosphorylation and NF-κB nuclear translocation in a caspase-dependent manner, and enhanced phosphorylated cyclic adenosine monophosphate response element-binding protein and phosphorylated Bcl2-associated death promoter levels to reduce cognitive impairment and apoptosis. Taken together, our results indicate that minocycline is a better choice for prolonged use in prion diseases and encourage its further clinical development as a possible treatment for this disease.

Failed communication between mitochondria and lysosomes causes dysfunctional mitochondria, which may induce mitochondria-related neurodegenerative diseases. Here, we show that RAB7A, a small GTPase of the Rab family, mediates the crosstalk between these two important organelles to maintain homeostasis in N2a cells treated with PrP 106–126 . Specifically, we demonstrate that mitophagy deficiency in N2a cells caused by PrP 106–126 is associated with dysregulated RAB7A localization in mitochondria. Cells lacking RAB7A display decreased mitochondrial colocalization with lysosomes and significantly increased mitochondrial protein expression, resulting in inhibited mitophagy. In contrast, overexpression of GTP-bound RAB7A directly induces lysosome colocalization with mitochondria. Further study revealed that GTP-bound RAB7A protects mitochondrial homeostasis by supporting autophagosome biogenesis. Moreover, we suggest that depletion of RAB7A leads to gross morphological changes in lysosomes, which prevents autophagosome–lysosome fusion and interferes with the breakdown of autophagic cargo within lysosomes. Overexpression of GTP-bound RAB7A can also alleviate PrP 106–126 -induced morphological damage and dysfunction of mitochondria, reducing neuronal apoptosis. Collectively, our data demonstrate that RAB7A successfully drives mitochondria to the autophagosomal lumen for degradation, suggesting that the communication of proteotoxic stress from mitochondria to lysosomes requires RAB7A, as a signaling molecule, to establish a link between the disturbed mitochondrial network and its remodeling. These findings indicate that small molecules regulating mitophagy have the potential to modulate cellular homeostasis and the clinical course of neurodegenerative diseases. Graphical Abstract Proposed model of mitophagy regulated by RAB7A. (1) Accumulating PrP 106–126 induced mitophagy. (2) RAB7A is recruited to mitochondria. (3) ATG5-12 and ATG9A (5) vesicles are recruited to the autophagosome formation sites in a RAB7A-dependent manner. The ATG5-12 complex recruits and anchors LC3-I to form active LC3-II (4), accelerating mitophagosomal formation. The ATG9A vesicles are thought to be a source of membranes for autophagosome assembly. The recruitment of proteins and lipids induces membrane expansion and subsequent closure to form the mitophagosome. (6) Maintenance of the normal low lysosomal PH depends on active (GTP-bound) RAB7A. (7) RAB7A recruits effector molecules responsible for tight membrane interactions, and directly or indirectly, the subsequent autophagosome merges with the lysosome, and the cargo is completely degraded.

Abstract Context Middle-aged to elderly patients with type 2 diabetes mellitus (T2DM) exhibit reduced functional connectivity and brain atrophy underlying cognitive decrements; however, little is known about brain abnormalities in young patients. Objective To detect brain anatomical and functional changes in young patients with T2DM during the early disease stage. Design Case-control study. Setting Tertiary referral hospital. Participants Thirty-five young patients with T2DM (<40 years of age) with no detectable microangiopathy and 32 nondiabetic control subjects. Intervention None. Main Outcome Measures Subjects underwent neuropsychological assessments and structural and resting-state functional MRI. Both voxel-based morphometry and resting-state functional connectivity analyses were performed. Results No significant differences in brain volume were observed between the patients with T2DM and the controls after controlling for age, sex, education, and body mass index. Compared with the controls, the patients showed greater connectivity of the left hippocampus with the left inferior frontal gyrus and the left inferior parietal lobule. Moreover, the enhanced functional connectivity of left hippocampus with the left inferior frontal gyrus significantly correlated with disease severity (urinary albumin-to-creatinine ratio) (r = 0.613, P < 0.001) and executive function (completion time of Stroop Color and Word Test) (r = −0.461, P = 0.005) after false discovery rate correction. Conclusions Our findings suggest an adaptive compensation of brain function to counteract the insidious cognitive decrements during the early stage of T2DM. Additionally, the functional alterations occurring before changes in brain structure and peripheral microangiopathy might serve as early biomarkers related to cognitive decrements. Enhanced hippocampal functional connectivity occurring prior to structural changes was found in young adults with T2DM, suggesting an adaptive brain compensation to counteract cognitive decrements.