Biology subjects

Hardy, J.

Publications and source records attributed to Hardy, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Long-read transcriptomic identification of synaptic adaptation to amyloid pathology in the App(NL-G-F) knock-in mouse model of the earliest phase of Alzheimer's disease

Genome-wide association studies (GWAS) have identified a transcriptional network of Alzheimers disease (AD) risk genes that are primarily expressed in microglia and are associated with AD pathology. However, traditional short-read sequencers have limited our ability to fully characterize how GWAS variants exert their effects on gene expression regulation or alternative splicing in response to the pathology, particularly resulting in inaccurate detection of splicing. To address this gap, we utilized long-read RNA-sequencing (RNA-seq) in the AppNL-G-F knock-in mouse model to identify changes in splicing and novel transcript isoforms in response to amyloid-{beta}. We show that long-read RNA-seq can recapitulate the expected induction of microglial expressed risk genes such as Trem2 in response to amyloid-{beta} at 9 months of age associated with ageing-dependent deficiencies in spatial short-term memory in the AppNL-G-F knock-in mice. Our results not only identified novel splicing events and transcript isoform abundance in genes associated with AD, but also revealed the complex regulation of gene expression through splicing in response to amyloid plaques. Surprisingly, the regulation of alternative splicing in response to amyloid was seen in genes previously not identified as AD risk genes, expressed in microglia, neurons and oligodendrocytes, and included genes such as Syngr1 that modulate synaptic physiology. We saw alternative splicing in genes such as Ctsa, Clta, Dennd2a, Irf9 and Smad4 in mice in response to amyloid, and the orthologues of these genes also showed transcript usage changes in human AD brains. Our data suggests a model whereby induction of AD risk gene expression associated with microglial proliferation and activation is concomitant with alternative splicing in a different class of genes expressed by microglia and neurons, which act to adapt or preserve synaptic activity in response to amyloid-{beta} during early stages of the disease. Our study provides new insights into the mechanisms and effects of the regulation of genes associated with amyloid pathology, which may ultimately enable better disease diagnosis, and improved tracking of disease progression. Additionally, our findings identify new therapeutic avenues for treatment of AD.

genetics↗

bioRxiv2024

The diversity of SNCA transcripts in neurons, and its impact on antisense oligonucleotide therapeutics

The role of the SNCA gene locus in driving Parkinsons disease (PD) through rare and common genetic variation is well-recognized, but the transcriptional diversity of SNCA in vulnerable cell types remains unclear. We performed SNCA long-read RNA sequencing in human dopaminergic neurons and show that annotated SNCA transcripts account for only 5% of expression. Rather, the majority of expression (75%) at the SNCA locus originates from transcripts with alternative 5 and 3 untranslated regions. Importantly, 10% originates from transcripts encoding open reading frames not previously annotated, which are translated and detectable in human postmortem brain. Defining the 3 untranslated regions enabled the rational design of antisense oligonucleotides targeting the majority of SNCA transcripts, leading to the effective reversal of PD pathology, including protein aggregation, mitochondrial dysfunction, and toxicity. Resolving the complexity of the SNCA transcriptional landscape impacts RNA therapies and highlights differences in protein isoforms and their contribution to disease.

neuroscience↗

bioRxiv2024

Neuronal downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease hallmarks

We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Out of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased A{beta} levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a 10-fold increased AD risk. PLCG2 LoF carriers exhibit low mRNA/protein PLCG2/PLC{gamma}2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single nuclei RNAseq analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexin in neurons. In conclusion, PLC{gamma}2 downregulation could increase AD risk by impairing synaptic functions and increasing the A{beta} levels and Tau phosphorylation in neurons.

neuroscience↗

bioRxiv2024

Large-scale visualisation of α-synuclein oligomers in Parkinson's disease brain tissue

Parkinsons disease (PD) is a common neurodegenerative condition characterised by the presence in the brain of large intraneuronal aggregates, known as Lewy bodies and Lewy neurites, containing fibrillar -synuclein. According to the amyloid hypothesis, these large end-stage species form from smaller soluble protein assemblies, often termed oligomers, which are proposed as early drivers of pathogenesis. To date, however, this hypothesis has remained controversial, at least in part because it has not been possible to directly visualise oligomeric aggregates in human brain tissue. Therefore, their presence, abundance and distributions have remained elusive. Here, we present ASA-PD (Advanced Sensing of Aggregates - Parkinsons Disease), an imaging method to generate large-scale -synuclein oligomer maps in post-mortem human brain tissue. We combined autofluorescence suppression with single-molecule fluorescence methods, which together, enable the detection of nanoscale -synuclein aggregates. To demonstrate the utility of this platform, we captured [~]1.2 million oligomers from the anterior cingulate cortex in human post-mortem brain samples from PD and healthy control patients. Our data revealed a specific subpopulation of nanoscale oligomers that represent an early hallmark of the proteinopathy that underlies PD. We anticipate that quantitative information about oligomer distributions provided by ASA-PD will enable mechanistic studies to reveal the pathological processes caused by -synuclein aggregation.

neuroscience↗

bioRxiv2024

Amelioration of signalling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia

Classic immunometabolic switching from oxidative phosphorylation (OXPHOS) to glycolysis occurs in myeloid cells such as microglia when encountering pathogenic insults. We previously showed that patient iPSC-derived microglia (iPS-Mg) harbouring the Alzheimers disease (AD) TREM2R47H hypomorph display deficits in the ability to metabolically switch from OXPHOS to glycolysis, with both reduced mitochondrial maximal respiration and glycolytic capacity. To resolve this, we generated common variant, TREM2R47H and TREM2-/- variant human iPS-Mg and we assessed the ability of supplementation with citrate or succinate, key metabolites and cell cycle breaking points upon microglia activation, to overcome deficits in a number of functions we identified previously as affected by TREM2 loss of function phenotypes. Succinate supplementation was more effective than citrate at overcoming mitochondrial deficits in OXPHOS and did not promote a switch to glycolysis. Citrate enhanced the lipid content of TREM2R47H iPS-Mg and was more effective at overcoming phagocytic deficits whereas succinate increased lipid content and phagocytic capacity in TREM2-/- iPS-Mg. Microglia cytokine release upon activation was differentially affected by citrate or succinate and neither metabolite altered soluble TREM2 shedding. Neither citrate nor succinate enhanced glycolysis but drove their effects through oxidative phosphorylation. Our data point to discrete pathway linkage between microglial metabolism and functional outcomes with implications for AD pathogenesis and treatments.

neuroscience↗

bioRxiv2024

DNA density is a better indicator of a nuclear bleb than lamin B loss

Nuclear blebs are herniations of the nucleus that occur in diseased nuclei that cause nuclear rupture leading to cellular dysfunction. Chromatin and lamins are two of the major structural components of the nucleus that maintain its shape and function, but their relative roles in nuclear blebbing remain elusive. Lamin B is reported to be lost in blebs by qualitative data while quantitative studies reveal a spectrum of lamin B levels in nuclear blebs dependent on perturbation and cell type. Chromatin has been reported to be decreased or de-compacted in nuclear blebs, but again the data are not conclusive. To determine the composition of nuclear blebs, we compared the immunofluorescence intensity of lamin B and DNA in the main nucleus body and nuclear bleb across cell types and perturbations. Lamin B nuclear bleb levels varied drastically across MEF wild type and chromatin or lamins perturbations, HCT116 lamin B1-GFP imaging, and human disease model cells of progeria and prostate cancer. However, DNA concentration was consistently decreased to about half that of the main nucleus body across all measured conditions. Using Partial Wave Spectroscopic (PWS) microscopy to measure chromatin density in the nuclear bleb vs body we find similar results that DNA is consistently less dense in nuclear blebs. Thus, our data spanning many different cell types and perturbations supports that decreased DNA is a better marker of a nuclear bleb than lamin B levels that vary widely.

cell biology↗

bioRxiv2023

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Progressive supranuclear palsy (PSP) is a rare Parkinsonian disorder characterized by problems with movement, balance, cognition, and other symptoms. PSP differs from Alzheimers disease (AD) and other neurodegenerative diseases displaying abnormal forms of the microtubule-associated protein tau ("tauopathies") by the presence of pathology not only in neurons, but also in astrocytes and oligodendrocytes. Genetic contributors may mediate these differences, however much of PSP genetics remains unexplained. Here we conducted the largest genome-wide association study (GWAS) of PSP to date including 2,779 cases (2,595 neuropathologically-confirmed) and 5,584 controls and identified six independent PSP susceptibility loci with genome-wide significant (p < 5x10-8) associations including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations revealed a unique oligodendrocytic signature that distinguishes PSP from AD and Parkinsons disease. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identified oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, as well as an association with elevated C4A expression in bulk brain tissue which may be driven by increased C4A copy number in PSP cases. Finally, histological studies demonstrated abnormal tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies including epigenomic and eQTL analyses, we identified potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in the pathogenesis of PSP.

neuroscience↗

bioRxiv2023

Differential LRRK2 signalling and gene expression in WT-LRRK2 and G2019S-LRRK2 mouse microglia treated with zymosan and MLi2.

IntroductionMutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene cause autosomal dominant Parkinsons disease (PD) with the most common causative mutation being the LRRK2 p.G2019S within the kinase domain. LRRK2 protein is highly expressed in the human brain and also in the periphery, and high expression of dominant PD genes in immune cells suggest involvement of microglia and macrophages in inflammation related to PD. LRRK2 is known to respond to extracellular signalling including TLR4 resulting in alterations in gene expression, with the response to TLR2 signalling through zymosan being less known. MethodsHere, we investigated the effects of zymosan, a TLR2 agonist and the potent and specific LRRK2 kinase inhibitor MLi-2 on gene expression in microglia from LRRK2-WT and LRRK2 p.G2019S knock-in mice by RNA-Sequencing analysis. ResultsWe observed both overlapping and distinct zymosan and MLi-2 mediated gene expression profiles in microglia. At least two candidate Genome-Wide Association (GWAS) hits for PD, CathepsinB (Ctsb) and Glycoprotein-nmb (Gpnmb), were notably downregulated by zymosan treatment. Genes involved in inflammatory response and nervous system development were up and downregulated respectively with zymosan treatment while MLi-2 treatment particularly exhibited upregulated genes for ion transmembrane transport regulation. Furthermore, we observed the top twenty most significantly differentially expressed genes in LRRK2 p.G2019S microglia show enriched biological processes in iron transport and response to oxidative stress. DiscussionOverall, these results suggest that microglial LRRK2 may contribute to PD pathogenesis through altered inflammatory pathways. Our findings should encourage future investigations of these putative avenues in the context of PD pathogenesis.

neuroscience↗

bioRxiv2023

Microglia produce the amyloidogenic ABri peptide in familial British dementia

Mutations in ITM2B cause familial British, Danish, Chinese and Korean dementias. In familial British dementia (FBD) a mutation in the stop codon of the ITM2B gene (also known as BRI2) causes a C-terminal cleavage fragment of the ITM2B/BRI2 protein to be extended by 11 amino acids. This fragment, termed amyloid-Bri (ABri), is highly insoluble and forms extracellular plaques in the brain. ABri plaques are accompanied by tau pathology, neuronal cell death and progressive dementia, with striking parallels to the aetiology and pathogenesis of Alzheimers disease. The molecular mechanisms underpinning FBD are ill-defined. Using patient-derived induced pluripotent stem cells, we show that expression of ITM2B/BRI2 is 34-fold higher in microglia than neurons, and 15-fold higher in microglia compared with astrocytes. This cell-specific enrichment is supported by expression data from both mouse and human brain tissue. ITM2B/BRI2 protein levels are higher in iPSC-microglia compared with neurons and astrocytes. Consequently, the ABri peptide was detected in patient iPSC-derived microglial lysates and conditioned media but was undetectable in patient-derived neurons and control microglia. Pathological examination of post-mortem tissue support ABri expression in microglia that are in proximity to pre-amyloid deposits. Finally, gene co-expression analysis supports a role for ITM2B/BRI2 in disease-associated microglial responses. These data demonstrate that microglia are the major contributors to the production of amyloid forming peptides in FBD, potentially acting as instigators of neurodegeneration. Additionally, these data also suggest ITM2B/BRI2 may be part of a microglial response to disease, motivating further investigations of its role in microglial activation. This has implications for our understanding of the role of microglia and the innate immune response in the pathogenesis of FBD and other neurodegenerative dementias including Alzheimers disease.

neuroscience↗

bioRxiv2023

Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci

Splicing quantitative trait loci (QTLs) have been implicated as a common mechanism underlying complex trait associations. However, utilising splicing QTLs in target discovery and prioritisation has been challenging due to extensive data normalisation which often renders the direction of the genetic effect as well as its magnitude difficult to interpret. This is further complicated by the fact that strong expression QTLs often manifest as weak splicing QTLs and vice versa, making it difficult to uniquely identify the underlying molecular mechanism at each locus. We find that these ambiguities can be mitigated by visualising the association between the genotype and average RNA sequencing read coverage in the region. Here, we generate these QTL coverage plots for 1.7 million molecular QTL associations in the eQTL Catalogue identified with five quantification methods. We illustrate the utility of these QTL coverage plots by performing colocalisation between vitamin D levels in the UK Biobank and all molecular QTLs in the eQTL Catalogue. We find that while visually confirmed splicing QTLs explain just 6/53 of the colocalising signals, they are significantly less pleiotropic than eQTLs and identify a prioritised causal gene in 4/6 cases. All our association summary statistics and QTL coverage plots are freely available at https://www.ebi.ac.uk/eqtl/.

genomics↗

bioRxiv2022

Pseudogenes limit the identification of novel common transcripts generated by their parent genes

The human genome contains numerous duplicated regions, such as parent-pseudogene pairs, causing sequencing reads to align equally well to either gene. The extent to which this ambiguity complicates transcriptomic analyses is currently unknown. This is concerning as many parent genes have been linked to disease, including GBA1, causally linked to both Parkinsons and Gaucher disease. We find that most of the short sequencing reads that map to GBA1, also map to its pseudogene, GBAP1. Using long-read RNA-sequencing in human brain, where all reads mapped uniquely, we demonstrate significant differences in expression compared to short-read data. We identify novel transcripts from both GBA1 and GBAP1, including protein-coding transcripts that are translated in vitro and detected in proteomic data, but that lack GCase activity. By combining long-read with single-nuclear RNA-sequencing to analyse brain-relevant cell types we demonstrate that transcript expression varies by brain region with cell-type-selectivity. Taken together, these results suggest a non-lysosomal function for both GBA1 and GBAP1 in brain. Finally, we demonstrate that inaccuracies in annotation are widespread among parent genes, with implications for many human diseases.

genetics↗

bioRxiv2022

What does heritability of Alzheimer's disease represent?

INTRODUCTIONBoth Alzheimers disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. METHODSWe compute heritability in five large independent cohorts (N=7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set. RESULTSSNP-based heritability of Alzheimers disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD=8%] on average when the APOE region is excluded and an additional 1% [SD=3%] when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts. CONCLUSIONThe heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes. Author SummaryEstimates of heritability in Alzheimers disease, the proportion of phenotypic variance explained by genetics, are very varied across different studies, therefore, the amount of missing heritability not yet captured by current genome-wide association studies is debated. We investigate this in five independent cohorts, provide estimates based on these cohorts and detail necessary suggestions to accurately calculate heritability in age-related disorders. We also confirm the importance of microglia relevant genetic markers in Alzheimers disease. This manuscript provides suggestions for other researchers computing heritability in late-onset disorders and the microglia gene-set used in this study will be published alongside this manuscript and made available to other researchers. The correct assessment of disease heritability will aid in better understanding the amount of missing heritability in Alzheimers disease.

genetics↗

bioRxiv2022

Genome-wide analysis of Structural Variants in Parkinson's Disease using Short-Read Sequencing data

Parkinsons disease is a complex neurodegenerative disorder, affecting approximately one million individuals in the USA alone. A significant proportion of risk for Parkinsons disease is driven by genetics. Despite this, the majority of the common genetic variation that contributes to disease risk is unknown, in-part because previous genetic studies have focussed solely on the contribution of single nucleotide variants. Structural variants represent a significant source of genetic variation in the human genome. However, because assay of this variability is challenging, structural variants have not been cataloged on a genome-wide scale, and their contribution to the risk of Parkinsons disease remains unknown. In this study, we 1) leveraged the GATK-SV pipeline to detect and genotype structural variants in 7,772 short-read sequencing data and 2) generated a subset of matched whole-genome Oxford Nanopore Technologies long-read sequencing data from the PPMI cohort to allow for comprehensive structural variant confirmation. We detected, genotyped, and tested 3,154 "high-confidence" common structural variant loci, representing over 412 million nucleotides of non-reference genetic variation. Using the long-read sequencing data, we validated three structural variants that may drive the association signals at known Parkinsons disease risk loci, including a 2kb intronic deletion within the gene LRRN4. Further, we confirm that the majority of structural variants in the human genome cannot be detected using short-read sequencing alone, encompassing on average around 4 million nucleotides of inaccessible sequence per genome. Therefore, although these data provide the most comprehensive survey of the contribution of structural variants to the genetic risk of Parkinsons disease to date, this study highlights the need for large-scale long-read datasets to fully elucidate the role of structural variants in Parkinsons disease.

genetics↗

bioRxiv2022

Analysis of nucleus and cytoplasm-specific RNA fractions demonstrates that a significant proportion of the genetic regulation of gene expression across the human brain occurs post-transcriptionally

Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of steady-state RNA in human brain, but not distinguishing between molecular processes regulating transcription and stability. RNA quantification within cellular fractions can disentangle these processes in cell types and tissues which are challenging to model in vitro. We investigated the underlying molecular processes driving the genetic regulation of gene expression specific to a cellular fraction using allele-specific expression (ASE). Applying ASE analysis to genomic and transcriptomic data from paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control human brains, we demonstrate that a significant proportion of genetic regulation of gene expression occurs post-transcriptionally in the cytoplasm, with genes undergoing this form of regulation more likely to be synaptic. These findings have implications for understanding the structure of gene expression regulation in human brain, and importantly the interpretation of rapidly growing single-nucleus brain RNA-sequencing and eQTL datasets, where cytoplasm-specific regulatory events could be missed.

genomics↗

bioRxiv2022

Gla-domain mediated targeting of externalized phosphatidylserine for intracellular delivery

Phosphatidylserine (PS) is a negatively charged phospholipid normally localized to the inner leaflet of the plasma membrane of cells but is externalized onto the cell surface during apoptosis as well as in malignant and infected cells. Consequently, PS may comprise an important molecular target in diagnostics, imaging and targeted delivery of therapeutic agents. While an array of PS binding-molecules exist, their utility has been limited by their inability to recognize PS and internalize diagnostic or therapeutic payloads. We describe the generation, isolation, characterization, and utility of a PS binding motif comprised of a carboxylated glutamic acid (GLA) residue domain, that both recognizes cell surface-exposed PS and is internalized into these cells after binding. Internalization is independent of the traditional endosomal-lysosomal pathway, directly entering the cytosol of the target cell in a rapid and energy-independent fashion. We demonstrate that this PS recognition extends to extracellular vesicles and stem cells and that GLA-domain conjugated probes can be detected upon intravenous administration in animal models of infectious disease and cancer. GLA domain binding and internalization offers new opportunities for targeting specific cells for imaging and delivery of therapeutics.

cell biology↗

bioRxiv2022

Glucocorticoid receptor activation during human microglial differentiation leads to genomic instability and senescence

Early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in children. Increasingly, the importance of microglia in these disorders has been recognised. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre-expoure of human iPS-microglia to GCs during primitive haematopoiesis (the critical stage of iPS-microglial differentiation) and then examined how this exposure affected the microglial phenotype as they differentiated and matured to microglia. The iPS-microglia predominately expressed glucocorticoid receptors over mineralocorticoid receptors, and the GR- splice variant. Chronic GCs exposure during primitive haematopoiesis was able to recapitulate in vivo ELS effects. Thus pre-exposure to prolonged GCs resulted in increased type I interferon signalling, the presence of Cyclic GMP-AMP synthase-positive (cGAS) micronuclei, and cellular senescence in the matured iPS-microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC-mediated ELS- associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autistic spectrum disorder. HighlightsO_LIHuman iPS-derived-microglia predominantly express glucocorticoid receptor NR3C1 compared with mineralocorticoid receptor NR3C2, and a predominant splice variant of the NR3C1 of GR-. C_LIO_LIGC expression shows a differentiation-linked increment from iPSC to iPS-microglia. C_LIO_LIAn early-life stress model was established by exposing iPSC to glucocorticoids during primitive haematopoiesis. C_LIO_LIRNA-seq analysis revealed that this early glucocorticoid exposure led to enhanced type I interferon inducible gene expression in the subsequent iPS-microglia. C_LIO_LIFurthermore, micronuclei formation and cellular senescence markers were upregulated in the iPSC-microglia, indicating genomic instability due to early chronic GC exposure. C_LIO_LIThese findings have ramifications for the microglial responses in ELS linked neurodevelopmental disorders such as schizophrenia, attention-deficit hyperactivity disorder and autistic spectrum disorder. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/493044v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@27854aorg.highwire.dtl.DTLVardef@9fc488org.highwire.dtl.DTLVardef@11fdfeaorg.highwire.dtl.DTLVardef@1a5a74f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Bacterial Infection of the Placenta Induces Sex-Specific Responses in the Fetal Brain

BACKGROUNDEpidemiological data indicate that prenatal infection is associated with an increased risk of several neurodevelopmental disorders in the progeny. These disorders display sex differences in presentation. The role of the placenta, which is a target of prenatal infection, in the sex-specificity of neurodevelopmental abnormalities is unknown. We used an imaging-based animal model of the bacterial pathogen Listeria monocytogenes to identify sex-specific effects of placental infection on neurodevelopment of the fetus. METHODSPregnant CD1 mice were infected with a bioluminescent strain of Listeria on embryonic day 14.5 (E14.5). Excised fetuses were imaged on E18.5 to identify the infected placentas. The associated fetal brains were analyzed for gene expression and altered brain structure due to infection. The behavior of adult offspring affected by prenatal Listeria infection was analyzed. RESULTSPlacental infection induced sex-specific alteration of gene expression patterns in the fetal brain and resulted in abnormal cortical development correlated with placental infection levels. Furthermore, male offspring exhibited abnormal social interaction, whereas females exhibited elevated anxiety. CONCLUSIONPlacental infection by Listeria induced sex-specific abnormalities in neurodevelopment of the fetus. Prenatal infection also affected the behavior of the offspring in a sex-specific manner. ImpactO_LIPlacental infection with Listeria monocytogenes induces sexually dichotomous gene expression patterns in the fetal brain. C_LIO_LIAbnormal cortical lamination is correlated with placental infection levels. C_LIO_LIPlacental infection results in autism related behavior in male offspring and heightened anxiety level in female offspring. C_LI

microbiology↗

bioRxiv2022

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions. We used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimers disease, amyotrophic lateral sclerosis and Parkinsons disease. We found no evidence for enrichment of positively-selected SNPs in the heritability of Alzheimers disease, amyotrophic lateral sclerosis and Parkinsons disease,, suggesting that common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk. These findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.

neuroscience↗