In December 2019, a novel disease, coronavirus disease 19 (COVID-19), emerged in Wuhan, People’s Republic of China. COVID-19 is caused by a novel coronavirus (SARS-CoV-2) presumed to have jumped species from another mammal to humans. This virus has caused a rapidly spreading global pandemic. To date, over 300,000 cases of COVID-19 have been reported in England and over 40,000 patients have died. While progress has been achieved in managing this disease, the factors in addition to age that affect the severity and mortality of COVID-19 have not been clearly identified. Recent studies of COVID-19 in several countries identified links between air pollution and death rates. Here, we explored potential links between major fossil fuel-related air pollutants and SARS-CoV-2 mortality in England. We compared current SARS-CoV-2 cases and deaths from public databases to both regional and subregional air pollution data monitored at multiple sites across England. After controlling for population density, age and median income, we show positive relationships between air pollutant concentrations, particularly nitrogen oxides, and COVID-19 mortality and infectivity. Using detailed UK Biobank data, we further show that PM2.5 was a major contributor to COVID-19 cases in England, as an increase of 1 m3 in the long-term average of PM2.5 was associated with a 12% increase in COVID-19 cases. The relationship between air pollution and COVID-19 withstands variations in the temporal scale of assessments (single-year vs 5-year average) and remains significant after adjusting for socioeconomic, demographic and health-related variables. We conclude that a small increase in air pollution leads to a large increase in the COVID-19 infectivity and mortality rate in England. This study provides a framework to guide both health and emissions policies in countries affected by this pandemic.

In December 2019, a novel disease, coronavirus disease 19 (COVID-19), emerged in Wuhan, People’s Republic of China. COVID-19 is caused by a novel coronavirus (SARS-CoV-2) presumed to have jumped species from another mammal to humans. This virus has caused a rapidly spreading global pandemic. To date, thousands of cases of COVID-19 have been reported in England, and over 25,000 patients have died. While progress has been achieved in managing this disease, the factors in addition to age that affect the severity and mortality of COVID-19 have not been clearly identified. Recent studies of COVID-19 in several countries identified links between air pollution and death rates. Here, we explored potential links between major air pollutants related to fossil fuels and SARS-CoV-2 mortality in England. We compared current SARS-CoV-2 cases and deaths recorded in public databases to both regional and subregional air pollution data monitored at multiple sites across England. We show that the levels of multiple markers of poor air quality, including nitrogen oxides and sulphur dioxide, are associated with increased numbers of COVID-19-related deaths across England, after adjusting for population density. We expanded our analysis using individual-level data from the UK Biobank and showed that particulate matter contributes to increased infectivity. We also analysed the relative contributions of individual fossil fuel sources on key air pollutant levels. The levels of some air pollutants are linked to COVID-19 cases and adverse outcomes. This study provides a useful framework to guide health policies in countries affected by this pandemic.

Parkinson's disease (PD), an age-dependent neurodegenerative disease, is characterised by the selective loss of dopaminergic neurons in the substantia nigra (SN). Mitochondrial dysfunction is a hallmark of PD, and mutations in PINK1, a gene necessary for mitochondrial fitness, cause PD. Drosophila melanogaster flies with pink1 mutations exhibit mitochondrial defects and dopaminergic cell loss and are used as a PD model. To gain an integrated view of the cellular changes caused by defects in the PINK1 pathway of mitochondrial quality control, we combined metabolomics and transcriptomics analysis in pink1-mutant flies with human induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) with a PINK1 mutation. We observed alterations in cysteine metabolism in both the fly and human PD models. Mitochondrial dysfunction in the NPCs resulted in changes in several metabolites that are linked to cysteine synthesis and increased glutathione levels. We conclude that alterations in cysteine metabolism may compensate for increased oxidative stress in PD, revealing a unifying mechanism of early-stage PD pathology that may be targeted for drug development. This article has an associated First Person interview with the first author of the paper.

In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson’s disease caused by mutations in pink1 or parkin. The Perk branch of the unfolded protein response (UPR) has emerged as a major toxic process in neurodegenerative disorders causing a chronic reduction in vital proteins and neuronal death. In this study, we combined microarray analysis and quantitative proteomics analysis in adult flies overexpressing dPerk to investigate the relationship between the transcriptional and translational response to dPerk activation. We identified tribbles and Heat shock protein 22 as two novel Drosophila activating transcription factor 4 (dAtf4) regulated transcripts. Using a combined bioinformatics tool kit, we demonstrated that the activation of dPerk leads to translational repression of mitochondrial proteins associated with glutathione and nucleotide metabolism, calcium signalling and iron-sulphur cluster biosynthesis. Further efforts to enhance these translationally repressed dPerk targets might offer protection against Perk toxicity.

Eukaryotic Tribbles proteins are pseudoenzymes that regulate multiple aspects of intracellular signalling. Both Drosophila melanogaster and mammalian members of this family of pseudokinases act as negative regulators of insulin signalling. Mammalian tribbles pseudokinase (TRIB) genes have also been linked to insulin resistance and type 2 diabetes mellitus. Type 2 diabetes mellitus is associated with increased body weight, sleep problems and increased long-term mortality. Here, we investigated how manipulating the expression of Tribbles impacts body weight, sleep and mortality. We showed that the overexpression of Drosophila tribbles (trbl) in the fly fat body reduces both body weight and lifespan in adult flies without affecting food intake. Furthermore, it decreases the levels of Drosophila insulin-like peptide 2 (DILP2; ILP2) and increases night-time sleep. The three genes encoding TRIBs of mammals, TRIB1, TRIB2 and TRIB3, show both common and unique features. As the three human TRIB genes share features with Drosophila trbl, we further explored the links between TRIB genetic variants and both body weight and sleep in the human population. We identified associations between the polymorphisms and expression levels of the pseudokinases and markers of body weight and sleep duration. We conclude that Tribbles pseudokinases are involved in the control of body weight, lifespan and sleep.

SUMMARY: Parkinson’s disease (PD) is characterised by insoluble α-synuclein (αSyn) aggregates in Lewy bodies (LBs) within the substantia nigra, with cortical pathology appearing as the disease progresses. Late-stage LB deposition, cellular stress, and neuronal loss obscure disease-driving events, we therefore performed multi-regional transcriptomic and aggregate profiling in early-midstage PD brains (Braak 3–4), where cortical regions are pathologically unaffected. We report neuroimmune activation as an early PD feature, characterised by the expansion of a high- SNCA -expressing microglial state. This robust immune signature occurs prior to LB formation, but is associated with oligomeric αSyn within cortical microglia. In hiPSC-derived microglia, both endogenous αSyn oligomerisation, and exogenous oligomer uptake, trigger transcriptional reprogramming, characterised by interferon-driven inflammation, antigen presentation, and mitochondrial suppression, closely mirroring the early PD brain. These findings describe mechanisms by which αSyn oligomerisation potently initiates early neuroinflammation, highlighting a critical interplay between proteinopathy and immune activation at the earliest stages of disease.