Biology subjects

Bras, J.

Publications and source records attributed to Bras, J..

5 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↗

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↗

bioRxiv2018

Parkinson’s disease genetics: identifying novel risk loci, providing causal insights and improving estimates of heritable risk

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

genetics↗

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↗