Biology subjects

Guerreiro, R.

Publications and source records attributed to Guerreiro, R..

7 recordsLinked to original sources

bioRxiv2024

Ide copy number variant does not influence lesion size and mortality in two C57BL/6J mouse models of cerebrovascular ischemia nor in human cerebrovascular disease. An exploratory study

Contrary to the common belief, the most commonly used laboratory mouse inbred strains are shaped by a distinctive genetic and phenotypic diversity. In the past 10 years next generation sequencing unveiled a wide spectrum of genetic variants in different mouse inbred strains and the meticulous observation of researchers pointed to a variegate intra-and inter-strain phenotypic diversity. Although a genotype-phenotype correlation has been described for some traits, the relationship between several endophenotypes and causative genetic variability remains still unknown. Recently, we characterized the brain collateral plasticity in two brain ischemia C57BL/6J mouse models (i.e bilateral common carotid artery stenosis [BCCAS] and 60-min transient unilateral middle cerebral artery occlusion [MCAO]) and observed a Mendelian-like fashion of inheritance of the posterior communicating artery (PcomA) plasticity. Interestingly, a copy number variant (CNV) spanning Ide locus was reported to segregate in an analogous Mendelian-like pattern in the C57BL/6J colonies of the Jackson Laboratory. Given the critical role of Ide in vascular plasticity, Ide CNV was an excellent candidate to explain PcomA variability in C57BL/6J inbred mice. To investigate this hypothesis, we applied a combination of complementary techniques (i.e T2-weighted magnetic resonance imaging [MRI], time of flight [TOF] angiography [MRA], cerebral blood flow [CBF] imaging and histology) to characterize the collaterome in C57BL/6J BCCAS and MCAO mice and performed on these Taqman genotyping, exome sequencing, and RNA sequencing. We report an Ide CNV in a BCCAS mouse with 2 patent PcomAs. We then investigated the hypothesis that IDE gain and loss of function mutations may have influenced the vascular phenotype in a cohort of 438,250 cases and controls (UK Biobank) and 15,790 neurological patients (Genomics England), respectively. We identified four IDE CNVs resulting in a loss of function (LoF) in one patient with hereditary ataxia, a patient with hereditary congenital heart disease and two healthy individuals. In addition, we report four IDE LoF point mutations (p.Leu5X, p.Met394ValfsX29, p.Pro14SerfsX26, p.Leu889X) present in controls or inherited from healthy parents. Ide CNV and LoF variants do not crucially influence PcomA variability in C57BL/6J inbred mice and do not cause a vascular phenotype in humans.

genetics↗

bioRxiv2022

Brassicaceae display diverse photorespiratory carbon recapturing mechanisms

Carbon concentrating mechanisms enhance the carboxylase efficiency of the central photosynthetic enzyme rubisco by providing supra-atmospheric concentrations of CO2 in its surrounding. In the C4 photosynthesis pathway, this is achieved by combinatory changes to leaf biochemistry and anatomy. Carbon concentration by the photorespiratory glycine shuttle requires fewer and less complex modifications. It could represent an early step during evolution from C3 to C4 photosynthesis and an inspiration for engineering approaches. Plants displaying CO2 compensation points between 10 to 40 ppm are therefore often termed C3-C4 intermediates. In the present study, we perform a physiological, biochemical and anatomical survey of a large number of Brassicaceae species to better understand the C3-C4 intermediate phenotype. Our phylogenetic analysis suggested that C3-C4 metabolism evolved up to five times independently in the Brassicaceae. The efficiency of the pathways showed considerable variation between the species but also within species. Centripetal accumulation of organelles in the bundle sheath was consistently observed in all C3-C4 classified accessions indicating a crucial role of anatomical features for CO2 concentrating pathways. Leaf metabolite patterns were strongly influenced by the individual plant accessions, but accumulation of photorespiratory shuttle metabolites glycine and serine was generally observed. Analysis of PEPC activities suggests that C4-like shuttles have not evolve in the investigated Brassicaceae. HighlightOur physiological, biochemical and anatomical survey of Brassicaceae revels multiple evolution of C3-C4 intermediacy connected to variation in photorespiratory carbon recapturing efficiency and a distinct C3-C4 bundle sheath anatomy.

plant biology↗

bioRxiv2021

Prion-like α-synuclein pathology in the brains of infants: Krabbe disease as a novel seed-competent α-synucleinopathy

Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein -synuclein aggregates into Lewy bodies. To explore whether -synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to -synuclein localisation and expression of modifications associated with LBD. To determine whether -synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of -synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived -synuclein. These observations constitute the first report of prion-like -synuclein in the brain tissue of infants and challenge the putative view that -synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.

pathology↗

bioRxiv2020

How understudied populations have contributed to our understanding of Alzheimer's disease genetics

The majority of genome-wide association studies have been conducted using samples with a European genetic background. As a field, we acknowledge this limitation and the need to increase the diversity of populations studied. A major challenge when designing and conducting such studies is to assimilate large samples sizes so that we attain enough statistical power to detect variants associated with disease, particularly when trying to identify variants with low and rare minor allele frequencies. In this study, we aimed to illustrate the benefits, to genetic characterization of Alzheimers disease (AD), in researching currently understudied populations. This is important for both fair representation of world populations and the translatability of findings. To that end, we have conducted a literature search to understand the contributions of studies, on different populations, to AD genetics. We systematically quantified the number of studies identifying mutations in known disease-causing genes, in a world-wide manner, and discussed the contributions of research in understudied populations to the identification of novel genetic factors in this disease. Additionally, we compared the effects of genome-wide significant SNPs across populations by focusing on loci that show different association profiles between populations (a key example being APOE). This work functions to both highlight how understudied populations have furthered our understanding of AD genetics, and to help us gage our progress in understanding the genetic architecture of this disease in all populations.

genetics↗

bioRxiv2019

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia

Loss-of-function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2 and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on microglial metabolic function in human patient iPSC-derived-microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimers disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPAR{gamma}/p38MAPK signalling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as {beta}-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.

neuroscience↗

bioRxiv2018

Heritability and genetic variance of dementia with Lewy bodies

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinsons disease (PD) or Alzheimers disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

neuroscience↗

bioRxiv2018

A comprehensive assessment of benign genetic variability for neurodegenerative disorders

1AbstractOver the last few years, as more and more sequencing studies have been performed, it has become apparent that the identification of pathogenic mutations is, more often than not, a complex issue. Here, with a focus on neurodegenerative diseases, we have performed a survey of coding genetic variability that is unlikely to be pathogenic.\n\nWe have performed whole-exome sequencing in 478 samples derived from several brain banks in the United Kingdom and the United States of America. Samples were included when subjects were, at death, over 60 years of age, had no signs of neurological disease and were subjected to a neuropathological examination, which revealed no evidence of neurodegeneration. This information will be valuable to studies of genetic variability as a causal factor for neurodegenerative syndromes. We envisage it will be particularly relevant for diagnostic laboratories as a filter step to the results being produced by either genome-wide or gene-panel sequencing. We have made this data publicly available at www.alzforum.org/exomes/hex.

genomics↗