Biology subjects

Vielle, A.

Publications and source records attributed to Vielle, A..

6 recordsLinked to original sources

bioRxiv2026

Trisomy 21 cerebral organoids exhibit Alzheimer's disease amyloid and apolipoprotein E co-pathologies

Adults with Down syndrome (DS) develop Alzheimers disease (AD) brain pathology by age 40 due to triplication of the Amyloid Precursor Protein (APP) gene on chromosome 21. Inheritance of the apolipoprotein E-e4 (APOE4) allele of the APOE gene on chromosome 19 remains the greatest genetic risk factor for AD in the typical population, yet its role in DS-associated AD (DS-AD) neuropathogenesis in people with DS is unclear. We generated human induced pluripotent stem cell (hiPSC)-derived neurons, astrocytes, and cerebral organoids (COs) using cells from people with DS and from euploid individuals. Aged DS COs were smaller than aged euploid COs and showed robust amyloid-{beta} neuropathology that was positively correlated with the levels of apoE expression. We then captured extracellular vesicles (EVs) from the conditioned media of COs and observed a decrease in the levels of secreted AD-related proteins, including amyloid, contained within the EVs and in the media from which the EVs were isolated. We also identified distinct neuronal and astrocytic gene expression signatures in DS COs relative to euploid COs, including a set of genes known to interact with both APOE and APP at the gene and/or protein levels. Lastly, we determined that, despite differences in the expression levels of the specific genes involved, several common pathways were upregulated in T21 hiPSC-derived neurons, astrocytes, and COs, including apoptosis, the endolysosome, and structural stabilization pathways. Taken together, our findings provide novel insights into molecular mechanisms that may contribute to DS-AD and indicate that apoE plays an important role in the disease process.

neuroscience↗

bioRxiv2025

Developmental wave of programmed ganglion cell death in human retinal organoids

The delicate and complex structure of the neural retina that enables proper visual function is achieved during embryonic development through a precise balance of proliferation, differentiation, and cell death. Retinal ganglion cells (RGC), the only output neurons of the retina, show a steady increase in numbers during development except for two conserved waves of developmental cell death. However, the mechanisms responsible for these phenomena in the human retina are incompletely understood. In this work, we took advantage of human induced pluripotent stem cell (hiPSC)-derived retinal organoids to explore these questions. Using different markers and quantitative techniques in three different hiPSC lines, we found a consistent decrease in RGC numbers at week 8 of differentiation, corresponding to the timing of the early developmental wave described in other vertebrates. This decrease coincided with a peak in caspase 3 activation and TUNEL(+) staining, suggesting an apoptotic mechanism. Notably, this occurred without caspase 9 activation or an increased BAX/BCL2 ratio, but with elevated caspase 8 activation, indicating involvement of the extrinsic apoptotic pathway. Together, these results show for the first time the intrinsic ability of the human retina to regulate RGC numbers through programmed cell death, providing insight into conserved developmental mechanisms and informing the use of retinal organoids in basic and translational research.

developmental biology↗

bioRxiv2025

Developmental plasticity of hermaphrodite sperm production across environments in Caenorhabditis elegans

Many organisms show flexible resource allocation to adjust for optimal reproductive investment across different environments. How such reproductive plasticity occurs in hermaphroditic organisms--allocating resources to both oocytes and sperm--are central questions of sex allocation research. Self-fertilizing hermaphrodites of the androdioecious nematode Caenorhabditis elegans exhibit a sequential transition from spermatogenesis to oogenesis, so the extent of self-sperm production determines both fertilization onset and lifetime reproductive potential under selfing. Despite this key role, it remains largely unclear whether such sequential hermaphrodites flexibly adjust sperm production to optimize self-fertilization across different environments. Here we directly quantified plasticity in C. elegans hermaphrodite self-sperm production in diverse experimental environments. We found that: (a) Sperm production was developmentally plastic, but such changes did not consistently translate into changes in self-progeny number, suggesting C. elegans self-fecundity is often oocyte-limited rather than sperm-limited; (b) Contrary to expectations, plastically increased sperm production did not delay the onset of fertilization across various environments; (c) Subtle environmental challenges, such as mild dietary restriction, did not affect sperm production but had a significant impact on developmental time, age at reproductive maturity, and germline proliferation. This emphasizes the relative environmental insensitivity of sperm production compared to other reproductive traits in hermaphrodites. (d) Plasticity in sperm and germline traits varied by genetic background, with notable differences between the laboratory strain N2 and wild strains. These findings contribute to our understanding of reproductive plasticity in C. elegans and the developmental plasticity of sex allocation in sequential hermaphrodites.

evolutionary biology↗

bioRxiv2021

Traumatic Brain Injury Exacerbates Alzheimer's Disease Pathology in the Retinas of TgF344-AD Rats

Alzheimers disease (AD) is a neurodegenerative condition that affects 6.2 million people age 65 and older in the U.S. alone, and is the leading cause of dementia. Moreover, AD can lead to visual impairment, and AD histopathology also manifests in the retina. However, the factors that modulate AD pathophysiology and lead to varied susceptibility and presentation in the population are not well understood. In this context, traumatic brain injury (TBI), which can arise from sport concussions, military combat, and other causes, is associated with a 2.3-fold higher risk of developing AD and AD-related dementias (ADRD). Thus, we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology. Several animal models have been developed to investigate the mechanisms underlying AD, but many have been limited by imperfect recapitulation of human pathology, and no model of TBI-associated AD (AD-TBI) has been characterized. To address this gap, we generated an innovative model of AD-TBI by taking advantage of a transgenic rat model (Tg-F344-AD) shown to recapitulate the main features of human AD pathology, and combining it with a twotime unilateral controlled cortical impact paradigm to mimic repetitive mild TBI (rmTBI). Histopathological analyses at four months post-impact confirm the presence of AD markers in transgenic retinas, and an increased severity of AD pathology due to TBI. Together, these results contribute to our understanding of the effects of TBI on AD retinopathy, with implications for patient care and therapeutic development.

neuroscience↗

bioRxiv2020

A single nucleotide change underlies the genetic assimilation of a plastic trait

Genetic assimilation - the evolutionary process by which an ancestral environmentally sensitive phenotype is made constitutive - is a fundamental concept in biology. Its evolutionary relevance is debated, and our understanding of its prevalence, and underlying genetics and molecular mechanisms, is poor. Matricidal hatching is an extreme form of maternal provisioning induced by adverse conditions, which varies among Caenorhabditis elegans populations. We identified wild isolates, sampled from natural populations across multiple years and locations, that express a derived state of near-constitutive matricidal hatching. A single amino acid change in kcnl-1, encoding a small-conductance calcium-activated potassium channel subunit, explains most of this variation. A gain-of-function mutation altering the S6 transmembrane domain causes inappropriate activation of the K+ channel, leading to reduced vulval muscle excitability, and thus reduced expulsion of embryos, irrespective of environment. Using reciprocal allelic replacements, we show that this amino acid change is sufficient to induce constitutive matricidal hatching whilst re-establishing the ancestral protein abolishes matricidal hatching and restores egg-laying, thereby doubling lifetime reproductive fitness under benign conditions. While highly deleterious in the laboratory, experimental evolution showed that KNCL-1(V530L) is maintained under fluctuating resource availability. Selection on a single point mutation can therefore underlie the genetic assimilation of an ancestrally plastic trait with drastic life-history consequences.

evolutionary biology↗

bioRxiv2018

Evolution of sperm competition: Natural variation and genetic determinants of Caenorhabditis elegans sperm size

Sperm morphology is critical for sperm competition and thus for reproductive fitness. In the male-hermaphrodite nematode Caenorhabditis elegans, sperm size is a key feature of sperm competitive ability. Yet despite extensive research, the molecular mechanisms regulating C. elegans sperm size and the genetic basis underlying its natural variation remain unknown. Examining 97 genetically distinct C. elegans strains, we observe significant heritable variation in male sperm size but genome-wide association mapping did not yield any QTL (Quantitative Trait Loci). While we confirm larger male sperm to consistently outcompete smaller hermaphrodite sperm, we find natural variation in male sperm size to poorly predict male fertility and competitive ability. In addition, although hermaphrodite sperm size also shows significant natural variation, male and hermaphrodite sperm size do not correlate, implying a sex-specific genetic regulation of sperm size. To elucidate the molecular basis of intraspecific sperm size variation, we focused on recently diverged laboratory strains, which evolved extreme sperm size differences. Using mutants and quantitative complementation tests, we demonstrate that variation in the gene nurf-1 - previously shown to underlie the evolution of improved hermaphrodite reproduction - also explains the evolution of reduced male sperm size. This result illustrates how adaptive changes in C. elegans hermaphrodite function can cause the deterioration of a male-specific fitness trait due to a sexually antagonistic variant, representing an example of intralocus sexual conflict with resolution at the molecular level. Our results further provide first insights into the genetic determinants of C. elegans sperm size, pointing at an involvement of the NURF chromatin remodelling complex.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC=\"FIGDIR/small/501486v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (166K):\norg.highwire.dtl.DTLVardef@1ff917org.highwire.dtl.DTLVardef@11a5e4corg.highwire.dtl.DTLVardef@250996org.highwire.dtl.DTLVardef@1989580_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗