Alzheimer's and Parkinson's Diseases Predict Different COVID-19 Outcomes: A UK Biobank Study.

In December 2019, a coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began infecting humans, causing a novel disease, coronavirus disease 19 (COVID-19). This was first described in the Wuhan province of the People's Republic of China. SARS-CoV-2 has spread throughout the world, causing a global pandemic. To date, thousands of cases of COVID-19 have been reported in the United Kingdom, and over 45,000 patients have died. Some progress has been achieved in managing this disease, but the biological determinants of health, in addition to age, that affect SARS-CoV-2 infectivity and mortality are under scrutiny. Recent studies show that several medical conditions, including diabetes and hypertension, increase the risk of COVID-19 and death. The increased vulnerability of elderly individuals and those with comorbidities, together with the prevalence of neurodegenerative diseases with advanced age, led us to investigate the links between neurodegeneration and COVID-19. We analysed the primary health records of 13,338 UK individuals tested for COVID-19 between March and July 2020. We show that a pre-existing diagnosis of Alzheimer's disease predicts the highest risk of COVID-19 and mortality among elderly individuals. In contrast, Parkinson's disease patients were found to have a higher risk of SARS-CoV-2 infection but not mortality from COVID-19. We conclude that there are disease-specific differences in COVID-19 susceptibility among patients affected by neurodegenerative disorders

Alzheimer's and Parkinson's Diseases Predict Different COVID-19 Outcomes: A UK Biobank Study.

In December 2019, a coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began infecting humans, causing a novel disease, coronavirus disease 19 (COVID-19). This was first described in the Wuhan province of the People's Republic of China. SARS-CoV-2 has spread throughout the world, causing a global pandemic. To date, thousands of cases of COVID-19 have been reported in the United Kingdom, and over 45,000 patients have died. Some progress has been achieved in managing this disease, but the biological determinants of health, in addition to age, that affect SARS-CoV-2 infectivity and mortality are under scrutiny. Recent studies show that several medical conditions, including diabetes and hypertension, increase the risk of COVID-19 and death. The increased vulnerability of elderly individuals and those with comorbidities, together with the prevalence of neurodegenerative diseases with advanced age, led us to investigate the links between neurodegeneration and COVID-19. We analysed the primary health records of 13,338 UK individuals tested for COVID-19 between March and July 2020. We show that a pre-existing diagnosis of Alzheimer's disease predicts the highest risk of COVID-19 and mortality among elderly individuals. In contrast, Parkinson's disease patients were found to have a higher risk of SARS-CoV-2 infection but not mortality from COVID-19. We conclude that there are disease-specific differences in COVID-19 susceptibility among patients affected by neurodegenerative disorders

Links between air pollution and COVID-19 in England.

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

Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways.

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

The role of organelle crosstalk in a Drosophila model of Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterised by the loss of dopaminergic (DA) neurons, causing deficits in motor function. At present, mitochondrial dysfunction and the endoplasmic reticulum (ER) unfolded protein response (UPR) are perceived to be molecular features of PD. The UPR is an evolutionarily conserved adaptive cellular response to unfolded or misfolded proteins in the ER. Three ER-resident proteins sense the UPR, one of which is the protein kinase RNA (PKR)-like ER kinase (PERK). PERK activation leads to translational repression via phosphorylation of eukaryotic translation initiation factor-2 α (eIF2α) as well as activation of activating transcription factor 4 (ATF4). This triggers a transcriptional response, initially promoting cell survival. Eventually, the sustained activation of the UPR leads to cell death. PERK has also been reported to modulate mitochondrial function. The overarching aim of this thesis was to investigate the relationship between PERK kinase and mitochondrial dysfunction in the pathogenesis of PD using the fruit fly Drosophila melanogaster as a model organism. To characterise the Drosophila PERK (dPerk) expressional landscape, I combined microarray and quantitative proteomics analysis from adult flies overexpressing dPerk. Using this approach, I identified tribbles (trbl) and Heat shock protein 22 (Hsp22) as two novel Drosophila ATF4 (dAtf4) regulated transcripts. Furthermore, I established that dPerk expression leads to translational repression of several mitochondrial proteins. The mitochondria-ER tether ATPase Family AAA Domain Containing 3A (ATAD3A) has recently been suggested to function as a negative regulator of PERK in mammalian models. I show that the ATAD3A fly orthologue Belphegor (Bor) does not act as an inhibitor of dPerk. Furthermore, I propose that this is due to the lack of the proline-rich motif in Drosophila, otherwise present in the protein structure of its mammalian orthologue. Mutations in PTEN-induced putative kinase 1 (PINK1), a mitophagy gene, cause neurodegeneration in some autosomal recessive forms of PD. In Drosophila, mutations in the pink1 gene cause mitochondrial dysfunction and the degeneration of DA neurons. Pink1 mutants also show overactivation of the dPerk/eIF2α/dAtf4 axis. Therefore, I used the pink1 PD Drosophila model to further probe the role of dPerk in the pathomechanism of PD. PD patients experience gastrointestinal issues that often precede the onset of motor symptoms, implicating the gut-brain axis in the pathogenesis of this disease. Likewise, in pink1 mutants, mitochondrial dysfunction leads to cell death and proliferation in the Drosophila midgut. Suppressing intestinal dysfunction is neuroprotective. I found that the intestinal expression of dPerk causes intestinal damage, and silencing dPerk in the pink1 intestine leads to a rescue of intestinal dysfunction and neurodegeneration. The ER stress marker Trbl also acts as an inhibitor of Akt, implicating this pseudokinase as a negative regulator of insulin signalling. The human Trbl orthologue tribbles pseudokinase 3 (TRIB3) is upregulated in insulin resistant as well as obese adults, and TRIB3 polymorphisms are associated with type 2 diabetes and insulin resistance. The fat body is a fly organ homologous to the mammalian liver and adipose tissue. It functions to synthesise and store triacylglycerol and regulate endocrine and immune signalling, implicating it in the regulation of complex behaviours such as sleep. My results show that the FB expression of Trbl leads to metabolic defects, systemic repression of insulin signalling and a reduction in night-time sleep. This thesis investigates inter-organelle as well as inter-organ signalling using Drosophila melanogaster as a model organism. My research shows that the ER UPR kinase dPerk is an important regulator of mitochondrial function and intestinal homeostasis, suggesting dPerk as a potential therapeutic target for PD. Furthermore, analysis of Trbl pseudokinase function in Drosophila melanogaster proposes Trbl as a molecular link between animal nutrient state and behaviour

Alzheimer’s and Parkinson’s Diseases Predict Different COVID-19 Outcomes: A UK Biobank Study

In December 2019, a coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began infecting humans, causing a novel disease, coronavirus disease 19 (COVID-19). This was first described in the Wuhan province of the People’s Republic of China. SARS-CoV-2 has spread throughout the world, causing a global pandemic. To date, thousands of cases of COVID-19 have been reported in the United Kingdom, and over 45,000 patients have died. Some progress has been achieved in managing this disease, but the biological determinants of health, in addition to age, that affect SARS-CoV-2 infectivity and mortality are under scrutiny. Recent studies show that several medical conditions, including diabetes and hypertension, increase the risk of COVID-19 and death. The increased vulnerability of elderly individuals and those with comorbidities, together with the prevalence of neurodegenerative diseases with advanced age, led us to investigate the links between neurodegeneration and COVID-19. We analysed the primary health records of 13,338 UK individuals tested for COVID-19 between March and July 2020. We show that a pre-existing diagnosis of Alzheimer’s disease predicts the highest risk of COVID-19 and mortality among elderly individuals. In contrast, Parkinson’s disease patients were found to have a higher risk of SARS-CoV-2 infection but not mortality from COVID-19. We conclude that there are disease-specific differences in COVID-19 susceptibility among patients affected by neurodegenerative disorders

Upregulation of Tribbles decreases body weight and increases sleep duration.

Peer reviewed: TrueAcknowledgements: We thank the Vienna Drosophila RNAi Center, Bloomington Drosophila Stock Center, L. Dobens and A. Telemans for providing the fly stocks, and the Fly Facility, Department of Genetics, University of Cambridge, for supplying fly food and generating transgenic lines.Funder: University of Cambridge; Id: http://dx.doi.org/10.13039/501100000735Eukaryotic 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

Increased cysteine metabolism in PINK1 models of Parkinson's disease.

Peer reviewed: TrueFunder: AstraZeneca; Id: http://dx.doi.org/10.13039/100004325Funder: University of Cambridge; Id: http://dx.doi.org/10.13039/501100000735Parkinson'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