Biology subjects

Gaspar, L.

Publications and source records attributed to Gaspar, L..

9 recordsLinked to original sources

bioRxiv2025

Associations Between Frailty and Cognitive Outcomes Across the Lifespan of Mice

Advancements in monitoring biological and brain aging with precise measures of health and longevity have the potential to accelerate research on pharmacological, genetic, and aging-related interventions. Over the past decade, frailty index has been used as an assessment tool for rodents, evaluating more than 30 non-invasive parameters that are strongly associated with chronological age, correlated with mortality, and sensitive to lifespan-altering interventions. However, whether aging phenotypes captured by the frailty index reflect brain aging remains unclear. In this study, we examined the relationship between frailty index and cognitive ability in young (3-4 months), middle-aged (12 months), and old (24 months) male and female C57BL/6J mice using a battery of behavioral and locomotor assays to determine whether frailty index scores can predict performance in tasks evaluating behavioral and cognitive function. Among the behavioral assays tested, frailty index scores had good correlation with the percentage of time spent in the center of the open-field apparatus, the duration spent in the open arms of the elevated plus maze, and the time spent in the target hole of the Barnes maze. These findings indicate that the frailty index not only reflects general physiological aging but may also serve as a reliable predictor of age-related cognitive decline in mice, providing a valuable tool for studies of interventions targeting brain aging.

neuroscience↗

bioRxiv2025

DNA Break Induced Epigenetic Alterations Promote Plaque Formation and Behavioral Deficits in an Alzheimer's Disease Mouse Model

The dramatic increase in human longevity over recent decades has contributed to a rising prevalence of age-related diseases, including neurodegenerative disorders such as Alzheimers disease (AD). While accumulating evidence implicates DNA damage and epigenetic alterations in the pathogenesis of AD, their precise mechanistic role remains unclear. To address this, we developed a novel mouse model, DICE (Dementia from Inducible Changes to the Epigenome), by crossing the APP/PSEN1 (APP/PS1) transgenic AD model with the ICE (Inducible Changes to the Epigenome) model, which allows for the controlled induction of double-strand DNA breaks (DSBs) to stimulate aging-related epigenetic drift. We hypothesized that DNA damage induced epigenetic alterations could influence the onset and progression of AD pathology. After experiencing DNA damage for four weeks, DICE mice, together with control, ICE, and APP/PS1 mice, were allowed to recover for six weeks before undergoing a battery of behavioral assessments including the open-field test, light/dark preference test, elevated plus maze, Y-maze, Barnes maze, social interaction, acoustic startle, and pre-pulse inhibition (PPI). Molecular and histological analyses were then performed to assess A{beta} pathology and neuroinflammatory markers. Our findings reveal that DNA damage-induced epigenetic changes significantly affect cognitive behavior and alters A{beta} plaque morphology and neuroinflammation as early as six months of age. These results provide the first direct evidence that DNA damage can modulate amyloid pathology in a genetically susceptible AD model. Future studies will be aimed at investigating DNA damage- induced epigenetic remodeling across additional models of AD and neurodegeneration to further elucidate its role in brain aging and disease progression.

neuroscience↗

bioRxiv2025

Phylogenomic analyses of the diverse desert-alpine plant lineage Cistantheae

Deserts and alpine habitats, though ecologically distinct, share similar environmental stressors such as drought and high radiation. Various plant lineages traverse both biomes, which is often associated with transitions in life history strategy, where annuality is more often associated with drier desert habitats and perenniality more common in higher elevations. One such lineage is Cistantheae (Montiaceae), a morphologically diverse herbaceous clade in western North and South America. We aimed to infer a robust phylogeny of the clade as a foundation for taxonomic and comparative work. We used double-digest RADSeq to generate reduced-representation genomic data from over 160 samples representing 48 putative species in Cistantheae. Maximum likelihood and coalescent-based phylogenetic methods were utilized to infer evolutionary relationships across the full clade and within major subclades. We tested for signatures of admixture and introgressive gene flow, and reconstructed ancestral life history and climate niche to identify patterns of correlated evolution. We inferred a well-resolved phylogeny of Cistantheae, providing strong support for relationships among subclades within Cistantheae. While many species relationships were clarified, we also found evidence of rampant gene flow and incomplete lineage sorting, particularly within the annual Cistanthe clade from the Atacama Desert. Life history is evolutionarily labile across the clade, and was strongly correlated with temperature/ precipitation-related bioclimatic variables: annuals tend to occur in hotter, drier environments, while perennials in cooler, wetter. Elevational range was also evolutionarily labile, with several species occupying broad elevational gradients. We present the first densely-sampled, phylogenomic analysis of Cistantheae, providing key insights into species relationships in the clade. Repeated transitions in life history and climate niche, alongside wide elevational ranges, suggest that many Cistantheae species may be preadapted to both arid and montane habitats. This phylogeny will underpin further comparative, taxonomic, and phylogenomic studies in this ecologically important lineage.

evolutionary biology↗

bioRxiv2025

Short-Term Exposure to Polystyrene Microplastics Alters Cognition, Immune, and Metabolic Markers in an APOE Genotype and Sex-Dependent Manner

Alzheimers disease (AD) is one of the most prevalent neurodegenerative disorders and one of the leading causes of death in individuals over the age of 65. Most cases of AD develop sporadically, however, there are several risk factors that have been identified which significantly increases an individuals risk for developing AD. The most prominent of these is Apolipoprotein E4 (APOE4), which can potentially result in an up to 10-fold greater risk of developing AD. The presence of APOE4 alone, however, cannot be solely responsible for AD as the disease may occur even in the absence of APOE4. Therefore, there must be other contributing factors such as exposure to environmental toxins including heavy metals and pesticides, which have independently been shown to contribute to AD. Nano- and microplastics (NMPs) are plastic particles less than 1 m and 5 mm in size, respectively, and have only recently been identified as a major environmental pollutant with serious health concerns. Given the adverse health effects that are increasingly being associated with NMPs exposure, we sought to understand how the combination of APOE4 and NMPs exposure may work synergistically to promote cognitive dysfunction and alter key regulatory pathways to impact overall health. Following an acute (3 week) exposure to pristine spherical fluorescently-labeled 0.1 and 2 {micro}m polystyrene (PS) NMPs, we found significant sex-dependent alterations in locomotor and recognition memory in APOE4 mice, but not in APOE3 controls. We additionally found that exposure to PS-NMPs resulted in sex and genotype specific alterations in astrocytic and microglial markers in the brain, and in CYP1A1, a major metabolizer of environmental polycyclic aromatic hydrocarbons, in the liver. These results suggest PS-NMPs may interact with the APOE4 allele to promote cognitive dysfunction and alter immune and metabolic pathways which may contribute to disease-like states.

neuroscience↗

bioRxiv2025

A novel inducible mtDNA mutator mouse model to study mitochondrial dysfunction with temporal and spatial control

Mitochondrial dysfunction is a hallmark of aging and numerous age-related diseases. A wealth of studies supports the accumulation of mitochondrial DNA (mtDNA) mutations as a contributing factor to mitochondrial dysfunction in aging and disease. One of the best models to study the relationship between mtDNA mutations and mitochondrial dysfunction is the mtDNA mutator mouse, which expresses a proofreading-deficient version of mtDNA polymerase-{gamma} (PolgA). Despite its groundbreaking contributions to mitochondrial biology and aging research, this model is limited by the whole-body accumulation of mtDNA mutations, which prevents the investigation of tissue-specific differences in mitochondrial dysfunction. To overcome this limitation, we developed a novel inducible knock-in mtDNA mutator mouse model that allows spatial and temporal control of mtDNA mutations, enabling the precise study of mitochondrial dysfunction in a tissue- and time-specific manner. Here, we report the generation and validation of this novel model through whole-body induction via Cre recombinase. Our data demonstrate that, upon induction, this model recapitulates the phenotype of the original mtDNA mutator mouse manifesting the same behavioral and biochemical alterations. This work establishes the functionality of our model and highlights its value as a powerful tool for studying the impact of mtDNA mutations with enhanced specificity and control.

genetics↗

bioRxiv2025

Circadian Rhythms are Disrupted in Patients and Preclinical Models of Machado-Joseph Disease

Machado-Joseph disease (MJD) is caused by an abnormal CAG repeat expansion in the ATXN3 gene, leading to the expression of a mutant ataxin-3 (mutATXN3) protein. MJD patients exhibit a wide range of clinical symptoms, including motor incoordination. Emerging evidence highlights circadian rhythm disruptions as early indicators and potential risk factors for the progression of neurodegenerative conditions. Circadian rhythms are regulated by internal clocks, with the suprachiasmatic nucleus (SCN) acting as the master pacemaker to synchronize timing across the bodys behavioural and physiological functions. While sleep disturbances have been observed in MJD, the role of clock regulation in its pathophysiology remains largely unexplored in spinocerebellar ataxias. This study aimed to investigate circadian rhythms, characterize associated disruptions, and uncover the mechanisms underlying clock dysregulation in patients and preclinical models of MJD. Circadian activity in MJD patients was assessed over two weeks using actigraphy, while in a YAC-MJD transgenic mouse model, circadian rhythms were examined through: (a) wheel-running experiments; (b) telemetry-based monitoring of core body temperature; (c) immunohistochemical analysis of the neuropeptides arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) in the SCN and paraventricular nucleus (PVN); and (d) RT-qPCR evaluation of clock gene expression in the cerebellum. The impact of mutATXN3 on clock mechanisms was further investigated using Bmal1/Per2-luciferase reporters. MJD patients exhibited a progressive decline in robustness of behavioural rhythms, demonstrated by negative correlations between the circadian function index, rest-activity fragmentation, and sleep efficiency with MJD clinical scales. YAC-MJD mice exhibited reduced activity levels, increased behavioural fragmentation, and required three additional days to re-entrain after a jet lag protocol, compared to controls. Disrupted core body temperature rhythms were observed, including a phase advance and elevated temperature ([~]1 {degrees}C) at the onset of the active period. Furthermore, transgenic mice showed reduced levels of VIP and AVP in the SCN and PVN, and decreased clock gene expression in the cerebellum. Lastly, we found new mechanistic evidence that WT ATXN3 activates the promoters of Bmal1 and Per2, whereas mutATXN3 loses the capacity to drive Per2 upon polyglutamine expansion. Overall, our findings indicate that central clock dysfunction in MJD is associated with impaired clock gene expression and disruptions in activity and temperature rhythms. This study provides the first robust evidence of circadian rhythm dysregulation and underlying mechanisms in MJD, paving the way for the identification of new biomarkers and the development of novel circadian-based interventions to tackle MJD and possibly other spinocerebellar ataxias. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/631212v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@25078dorg.highwire.dtl.DTLVardef@112e523org.highwire.dtl.DTLVardef@1818356org.highwire.dtl.DTLVardef@1d5a6c0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Small non-coding RNA content in plasma-derived extracellular vesicles distinguish ataxic SCA3 mutation carriers from pre-ataxic and control subjects

Spinocerebellar ataxia type 3 (SCA3), a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene, is the most common spinocerebellar ataxia subtype worldwide. Currently, there is no therapy to stop or prevent disease progression. Promising therapeutic strategies are emerging, but their translation into clinical practice requires sensitive and reliable biomarkers. Blood circulating extracellular vesicles constitute a promising source of biomarkers with potential to track alterations of the central nervous system due to their ability to cross the blood brain barrier. Here, we perform sequencing analysis of small RNAs from plasma-derived extracellular vesicles from SCA3 mutation carriers (10 pre-ataxic and 10 ataxic) and 12 control subjects to identify potential RNA biomarker candidates for this disease. Data showed that plasma-derived extracellular vesicles from ataxic SCA3 mutation carriers are enriched in mitochondrial, nuclear, and nucleolar RNA biotypes compared to pre-ataxic and control subjects. Moreover, ataxic mutation carriers could be discriminated from control and pre-ataxic subjects based on the miRNAs or piRNAs content, but not tRNA. Furthermore, we identified a subset of differentially expressed miRNAs and piRNAs that clearly differentiate ataxic mutation carriers from pre-ataxic and control subjects. These findings open new avenues for further investigation on the role of these RNAs in the pathogenesis of SCA3 and their potential as biomarkers for this disease.

neuroscience↗

bioRxiv2022

An autoregulatory feedback loop converging on H2A ubiquitination drives synovial sarcoma

The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of mSWI/SNF complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the SSX C-terminus, via its SSXRD domain, directs SS18-SSX chromatin binding independently of SS18. SSXRD specific targeting is mediated by interaction with mono ubiquitinated H2A (H2AK119ub1) and histone MacroH2A with which the fusion overlaps genome wide. Variant Polycomb Repressive Complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C-terminus not only depends on H2AK119ub1 for localization but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results reveal an SSX/PRC1 autoregulatory feedback loop that reinforces fusion chromatin binding and therefore its oncogenic activity, and could play a role in a wider range of cancers and physiological settings where SSX proteins are overexpressed.

cancer biology↗

bioRxiv2018

Genome-wide recombination map construction from single individuals using linked-read sequencing

Meiotic recombination is a major molecular mechanism generating genomic diversity. Recombination rates vary across the genome, often involving localized crossover \"hotspots\" and \"coldspots\". Studying the molecular basis and mechanism underlying this variation within and among individuals has been challenging due to the high cost and effort required to construct individualized genome-wide maps of recombination crossovers. In this study we introduce a new method to detect recombination crossovers across the genome from sperm DNA using Illumina sequencing of linked-read libraries produced using 10X Genomics technology. We leverage the long range information provided by the linked short reads to phase and assign haplotype states to each DNA molecule. When applied to DNA from gametes of a diploid organism, the majority of linked-read molecules can be used to faithfully reconstruct an individuals two haplotypes present at each location in the genome. A valuable rare fraction of molecules that span meiotic crossovers between the two chromosome haplotypes can then be isolated from the broader population of nonrecombinant molecules. Our pipeline, called ReMIX, allows us to characterize the genomic location and intensity of meiotic crossovers in a single individual and faithfully detects previously described recombination hotspots discovered by studies using mapping panels in mice. With a median crossover resolution of the mouse and stickleback being 15kb and 23kb respectively, ReMIX provides a powerful, high-throughput, low-cost approach to quantify recombination variation across the genome opening up numerous opportunities to study recombination variation with high genomic resolution in multiple individuals. ReMIX source code is available at at https://github.com/adreau/ReMIX.

genomics↗