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We have generated a novel transgenic mouse model on a C57BL/6J genetic background that coexpresses KM670/671NL mutated amyloid precursor protein and L166P mutated presenilin 1 under the control of a neuron‐specific Thy1 promoter element (APPPS1 mice). Cerebral amyloidosis starts at 6–8 weeks and the ratio of human amyloid (A)β42 to Aβ40 is 1.5 and 5 in pre‐depositing and amyloid‐depositing mice, respectively. Consistent with this ratio, extensive congophilic parenchymal amyloid but minimal amyloid angiopathy is observed. Amyloid‐associated pathologies include dystrophic synaptic boutons, hyperphosphorylated tau‐positive neuritic structures and robust gliosis, with neocortical microglia number increasing threefold from 1 to 8 months of age. Global neocortical neuron loss is not apparent up to 8 months of age, but local neuron loss in the dentate gyrus is observed. Because of the early onset of amyloid lesions, the defined genetic background of the model and the facile breeding characteristics, APPPS1 mice are well suited for studying therapeutic strategies and the pathomechanism of amyloidosis by cross‐breeding to other genetically engineered mouse models.

Propagation of tau pathology is linked with progressive neurodegeneration, but the mechanism underlying trans‐synaptic spread of tau is unknown. We show that stimulation of neuronal activity, or AMPA receptor activation, induces tau release from healthy, mature cortical neurons. Notably, phosphorylation of extracellular tau appears reduced in comparison with intracellular tau. We also find that AMPA‐induced release of tau is calcium‐dependent. Blocking pre‐synaptic vesicle release by tetanus toxin and inhibiting neuronal activity with tetrodotoxin both significantly impair AMPA‐mediated tau release. Tau secretion is therefore a regulatable process, dysregulation of which could lead to the spread of tau pathology in disease. This report provides evidence that stimulation of neuronal activity, or AMPA receptor activation, induces tau release from cortical neurons via a calcium‐dependent mechanism. Dysregulation of this process could lead to the spread of tau pathology in disease.

In this study, we develop a simple assay to identify mitophagy inducers on the basis of the use of fluorescently tagged mitochondria that undergo a colour change on lysosomal delivery. Using this assay, we identify iron chelators as a family of compounds that generate a strong mitophagy response. Iron chelation-induced mitophagy requires that cells undergo glycolysis, but does not require PINK1 stabilization or Parkin activation, and occurs in primary human fibroblasts as well as those isolated from a Parkinson's patient with Parkin mutations. Thus, we have identified and characterized a mitophagy pathway, the induction of which could prove beneficial as a potential therapy for several neurodegenerative diseases in which mitochondrial clearance is advantageous.

Allergic asthma rates have increased steadily in developed countries, arguing for an environmental aetiology. To assess the influence of gut microbiota on experimental murine allergic asthma, we treated neonatal mice with clinical doses of two widely used antibiotics—streptomycin and vancomycin—and evaluated resulting shifts in resident flora and subsequent susceptibility to allergic asthma. Streptomycin treatment had little effect on the microbiota and on disease, whereas vancomycin reduced microbial diversity, shifted the composition of the bacterial population and enhanced disease severity. Neither antibiotic had a significant effect when administered to adult mice. Consistent with the ‘hygiene hypothesis’, our data support a neonatal, microbiota‐driven, specific increase in susceptibility to experimental murine allergic asthma. Allergic asthma rates are increasing in developed countries, arguing for an environmental aetiology. Profound changes in gut microbiota are reported in response to treatment in early life with the widely used antibiotic vancomycin, influencing asthma susceptibility.

Mitochondria manganese superoxide dismutase (SOD2) is an important antioxidant enzyme, deficiency of which is associated with various human diseases. The known primary regulation of SOD2 is through transcriptional activation. Here, we report that SOD2 is acetylated at Lys 68 and that this acetylation decreases SOD2 activity. Mitochondrial deacetylase SIRT3 binds to, deacetylates and activates SOD2. Increase of reactive oxygen species (ROS) levels stimulates SIRT3 transcription, leading to SOD2 deacetylation and activation. SOD2‐mediated ROS reduction is synergistically increased by SIRT3 co‐expression, but is cancelled by SIRT3 depletion. These results reveal a new post‐translational regulation of SOD2 by means of acetylation and SIRT3‐dependent deacetylation in response to oxidative stress. Mitochondria manganese superoxide dismutase (SOD2) is a major antioxidant enzyme associated with several diseases. This study shows that SOD2 is inhibited by acetylation and activated by SIRT3‐mediated deacetylation in response to reactive oxygen species (ROS).

Mutations in phosphatase and tensin homologue‐induced kinase 1 (PINK1) cause recessively inherited Parkinson's disease (PD), a neurodegenerative disorder linked to mitochondrial dysfunction. In healthy mitochondria, PINK1 is rapidly degraded in a process involving both mitochondrial proteases and the proteasome. However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD‐linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. Using an unbiased RNA‐mediated interference (RNAi)‐based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin‐associated rhomboid‐like protease (PARL), m‐AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. These results highlight a new role for MPP in PINK1 import and mitochondrial quality control via the PINK1–Parkin pathway. Dysfunctional mitochondria express high surface levels of the Parkinson's disease‐linked protein PINK1, which in turn recruits Parkin for mitophagy. Fon and colleagues now show that levels of PINK1 are kept low in normal mitochondria through degradation by the mitochondrial processing peptidase (MPP).

Mutations in isocitrate dehydrogenases (IDHs) have a gain‐of‐function effect leading to R (−)‐2‐hydroxyglutarate ( R‐ 2HG) accumulation. By using biochemical, structural and cellular assays, we show that either or both R ‐ and S ‐2HG inhibit 2‐oxoglutarate (2OG)‐dependent oxygenases with varying potencies. Half‐maximal inhibitory concentration (IC 50 ) values for the R ‐form of 2HG varied from approximately 25 μM for the histone N ε ‐lysine demethylase JMJD2A to more than 5 mM for the hypoxia‐inducible factor (HIF) prolyl hydroxylase. The results indicate that candidate oncogenic pathways in IDH‐associated malignancy should include those that are regulated by other 2OG oxygenases than HIF hydroxylases, in particular those involving the regulation of histone methylation. The oncometabolite 2‐hydroxyglutarate (2‐HG) inhibits chromatin‐modifying oxygenases (as histone lysine demethylases) with greater potency than HIF hydroxylases. This suggests that 2‐HG‐associated oncogenic pathways involve the regulation of histone methylation, rather than an elevated HIF response.

Mitochondrial hyperfusion has recently been shown to function as a cellular stress response, providing transient protection against apoptosis and mitophagy. However, the mechanisms that mediate this response remain poorly understood. In this study, we demonstrate that oxidized glutathione (GSSG), the core cellular stress indicator, strongly induces mitochondrial fusion. Biochemical and functional experiments show that GSSG induces the generation of disulphide‐mediated mitofusin oligomers, in a process that also requires GTP hydrolysis. Our data outline the molecular events that prime the fusion machinery, providing new insights into the coupling of mitochondrial fusion with the cellular stress response. This report shows that oxidized glutathione (GSSG) strongly induces mitochondrial fusion by inducing the generation of disulfide‐mediated mitofusin oligomers in response to redox stress.

R‐spondins are secreted Wnt signalling agonists, which regulate embryonic patterning and stem cell proliferation, but whose mechanism of action is poorly understood. Here we show that R‐spondins bind to the orphan G‐protein‐coupled receptors LGR4 and LGR5 by their Furin domains. Gain‐ and loss‐of‐function experiments in mammalian cells and Xenopus embryos indicate that LGR4 and LGR5 promote R‐spondin‐mediated Wnt/β‐catenin and Wnt/PCP signalling. R‐spondin‐triggered β‐catenin signalling requires Clathrin, while Wnt3a‐mediated β‐catenin signalling requires Caveolin‐mediated endocytosis, suggesting that internalization has a mechanistic role in R‐spondin signalling. R‐spondins are secreted proteins known to synergize with Wnt signalling. The authors now show that R‐spondins are ligands for LGR4 and LGR5 orphan G‐protein‐coupled receptors. Binding of R‐spondins to LGRs positively regulates both Wnt/ ‐catenin and Wnt/PCP signalling pathways in vivo.

Porcine epidemic diarrhoea (PED) is a non‐zoonotic viral disease of pigs caused by a coronavirus and characterised by watery diarrhoea and weight loss. PED is not notifiable to the EU or World Organisation for Animal Health listed but it is notifiable at the national level in Finland, France, Ireland and Sweden. PED case reports from seven countries and PED surveillance and monitoring activities in thirteen countries were reported. This information was combined with an extensive literature review to provide an update on global PED occurrence, circulating strains and impact in 2014–2015. PED confirmed cases have been reported in North America, South America, Asia and Europe. PED virus (PEDV) sequences originating from EU pig herds indicate that the strains currently in circulation share nearly 100% sequence identity and have greater than 99% sequence identity with the reference INDEL (insertion/deletion) strain USA/OH851/2014. In 2014–2015, greater genetic variability has been reported in strains circulating in Asia compared with EU Member States and a non‐INDEL strain has been detected in the Ukraine in 2014. Data on impact confirms that mortality is higher in suckling piglets and diarrhoea is observed in all age groups. The reported impact is in agreement with that reported in EFSA AHAW Panel (2014) indicating that the impact of recently reported PED outbreaks in Asia and the USA seems to be more severe than that described in EU countries, although the impact of different PEDV strains is difficult to compare between one country and another, as impact is dependent not only on pathogenicity but also on factors such as biosecurity, herd size, farm management, sanitary status or herd immune status.