Biology subjects

Ye, X.

Publications and source records attributed to Ye, X..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Gut Microbe-Derived Trimethylamine Shapes Circadian Rhythms Through the Host Receptor TAAR5

Elevated levels of the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) are associated with cardiometabolic disease risk. However, the mechanism(s) linking TMAO production to human disease are incompletely understood. Initiation of the metaorganismal TMAO pathway begins when dietary choline and related metabolites are converted to trimethylamine (TMA) by gut bacteria. Gut microbe-derived TMA can then be further oxidized by host flavin-containing monooxygenases to generate TMAO. Previously, we showed that drugs lowering both TMA and TMAO protect mice against obesity via rewiring of host circadian rhythms. Although most mechanistic studies in the literature have focused on the metabolic end product TMAO, here we have instead tested whether the primary metabolite TMA alters host metabolic homeostasis and circadian rhythms via trace amine-associated receptor 5 (TAAR5). Remarkably, mice lacking the host TMA receptor (Taar5-/-) have altered circadian rhythms in gene expression, metabolic hormones, gut microbiome composition, and diverse behaviors. Also, mice genetically lacking bacterial TMA production or host TMA oxidation have altered circadian rhythms. These results provide new insights into diet-microbe-host interactions relevant to cardiometabolic disease, and implicate gut bacterial production of TMA and the host receptor that senses TMA (TAAR5) in the physiologic regulation of circadian rhythms in mice. HIGHLIGHTSO_LIMice lacking the host TMA receptor (Taar5-/-) have altered circadian rhythms. C_LIO_LITaar5-/- mice have altered innate behaviors in a time of day dependent manner. C_LIO_LIThe normal circadian oscillations in the gut microbiome are dysregulated in Taar5-/- mice. C_LIO_LIGenetic deletion of bacterial TMA production or host TMA oxidation shapes circadian rhythms. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/647082v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1608forg.highwire.dtl.DTLVardef@6a809aorg.highwire.dtl.DTLVardef@2131f7org.highwire.dtl.DTLVardef@1575559_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Inherent Specificity and Mutational Sensitivity as Quantitative Metrics for RBP Binding

RNA-binding proteins (RBPs) regulate every aspect of post-transcriptional gene expression, yet our ability to compare how selectively different RBPs recognize their targets remains limited. Binding affinity, expressed as a dissociation constant, provides a universal quantity for comparing binding strength, but no equivalent metric exists for binding specificity. Here we introduce two quantitative metrics to fill this gap: inherent specificity, which measures how selectively an RBP distinguishes its strongest binding motif from all other sequences, and variation sensitivity, which measures tolerance to single nucleotide changes within that motif. Analyzing high-throughput sequencing data across 100 RBPs in vitro and 27 in cells, we find strong correspondence between in vitro and cellular measurements for sequence-driven RBPs. Domain swap CLIP experiments demonstrate that specificity can be transferred between protein contexts. Mathematical modeling and cellular competition experiments reveal that low-specificity RBPs can paradoxically sharpen the target discrimination of high-specificity partners by occupying non-preferred sites, an emergent property not predictable from affinity alone. These metrics and accompanying R packages provide a practical framework for comparing RBP binding behaviors and modeling how RBPs compete for RNA targets across the transcriptome.

molecular biology↗

bioRxiv2025

Natural product-mediated reaction hijacking mechanism validates Plasmodium aspartyl-tRNA synthetase as an antimalarial drug target

Malaria poses an enormous threat to human health. With ever-increasing resistance to currently deployed antimalarials, new targets and starting point compounds with novel mechanisms of action need to be identified. Here, we explore the antimalarial activity of the Streptomyces sp natural product, 5'-O-sulfamoyl-2-chloroadenosine (dealanylascamycin, DACM) and compare it with the synthetic adenosine monophosphate (AMP) mimic, 5-O-sulfamoyladenosine (AMS). These nucleoside sulfamates exhibit potent inhibition of P. falciparum growth with an efficacy comparable to that of the current front-line antimalarial dihydroartemisinin. Exposure of P. falciparum to DACM leads to inhibition of protein translation, driven by eIF2 phosphorylation. We show that DACM targets multiple amino acyl tRNA synthetase (aaRS) targets, including the cytoplasmic aspartyl tRNA synthetase (AspRS). The mechanism involves hijacking of the reaction product, leading to the formation of a tightly bound inhibitory amino acid-sulfamate conjugate. We show that recombinant P. falciparum and P. vivax AspRS are susceptible to hijacking by DACM and AMS, generating Asp-DACM and Asp-AMS adducts that stabilize these proteins. By contrast, human AspRS appears less susceptible to hijacking. X-ray crystallography reveals that apo P. vivax AspRS exhibits a stabilized flipping loop over the active site that is poised to bind substrates. By contrast, human AspRS exhibits disorder in an extended region around the flexible flipping loop as well as in a loop in motif II. These structural differences may underpin the decreased susceptibility of human AspRS to reaction-hijacking by DACM and AMS. Our work reveals Plasmodium AspRS as a promising antimalarial target and highlights structural features that underpin differences in the susceptibility of aaRSs to reaction hijacking inhibition.

biochemistry↗

bioRxiv2025

Rational design of potent small molecule SMARCA2/A4 (BRM/BRG1) degraders acting via the recruitment of FBXO22

Target-anchored monovalent degraders are more drug-like than their bivalent counterparts, Proteolysis Targeting Chimeras (PROTACs), while offering greater target specificity control than the E3 ligase-anchored monovalent degraders, also known as molecular glues. However, their discovery has typically been serendipitous, and the rules governing their identification remain unclear. This study focused on the intentional discovery of SMARCA2/A4 monovalent degraders using a library based on SMARCA2/A4 bromodomain-binding ligands. Compound G-6599 emerged as a lead candidate, showing exceptional degradation potency and specificity for SMARCA2/A4. Mechanistic studies revealed that G-6599 operates through the ubiquitin-proteasome pathway and the E3 ligase FBXO22. G-6599 was shown to promote ternary complex formation between SMARCA2 and FBXO22 involving covalent conjugation to a cysteine residue on the latter. Unlike other recently identified FBXO22-dependent degraders, it does not require biotransformation. The selective degradation ability of G-6599, along with its unique mechanism, highlights the therapeutic potential of target-anchored monovalent degraders.

cancer biology↗

bioRxiv2025

Molecular interactome of HNRNPU reveals regulatory networks in neuronal differentiation and DNA methylation

HNRNPU is an RNA-binding protein with diverse roles in transcriptional and post-transcriptional regulation. Pathogenic genetic variants of HNRNPU cause a severe neurodevelopmental disorder (NDD), but the underlying molecular mechanisms are unclear. Here, we comprehensively investigate the HNRNPU molecular interactome by integrating protein-protein interaction (PPI) mapping, RNA target identification, and genome-wide DNA methylation profiling in human neuroepithelial stem cells and differentiating neural cells. We identified extensive HNRNPU-centered networks, including a strong association with the mammalian SWI/SNF chromatin-remodelling complex, and uncovered a previously unrecognized role in translation. We present evidence that HNRNPU associates with mRNAs encoding proteins important for neuronal development, including several linked to NDDs. Silencing HNRNPU reprogrammed methylation dynamics at regulatory regions, particularly at active and bivalent promoters of neurodevelopmental transcription factors. Integrative analysis across PPI, RNA, and methylome datasets identified 19 converging genes at all three molecular levels, including NDD genes within the SWI/SNF complex and RNA-processing machinery such as SYNCRIP. Together, these data showcase HNRNPU as a central coordinator of RNA metabolism and epigenetic remodelling during neural differentiation, linking RNA-binding, chromatin organization, and DNA methylation to the pathogenesis of HNRNPU-related NDDs.

molecular biology↗

bioRxiv2025

Generalization but not strengthening of negative memories drives the development of depression-like behaviors

Individuals with depression exhibit intensified and generalized negative memories. However, how prior memories actually influence onset and/or progression of depression, particularly whether the strengthening or the generalization of prior memories play a key role, is poorly understood. Here, we introduced behavioral paradigms to differentiate between memory strengthening and generalization, and found that negative experiences that produced memory overgeneralization, but not strengthening, induced depression-like behaviors. Furthermore, we identified that the medial prefrontal cortex (mPFC) to the bed nucleus of the stria terminals (BNST) projection functionally linked memory generalization to depression, together with single-cell calcium imaging which revealed a significant overlap in the mPFCBNST neuronal ensemble encoding depression-like behaviors with that encoding generalized memory, but not memory strength. Circuit-based transcriptomic analysis and chromophore-assisted light inactivation demonstrated that triggering actin remodeling in the mPFCBNST neurons, a memory consolidation mechanism enhanced generalization while reducing memory strength, also induced depression-like behaviors. Collectively, these findings suggest generalization of negative memories as a primary factor that drives depression-like behaviors, highlighting the importance of early identification of individuals at risk for depression who exhibit overgeneralized negative memories, and targeting overgeneralized negative memories in the treatment of depression.

animal behavior and cognition↗

bioRxiv2025

A Preliminary Application of Bird Surveys Using Environmental DNA Technology: in Futian Mangrove Nature Reserve

Futian Mangrove Nature Reserve is a vital habitat for birds in Shenzhen city of China, and the diversity of bird species is of considerable concern. Traditional surveys depend on direct observation and expert assessment, necessitating significant manpower for tracking. This study utilized environmental DNA metabarcoding technology to gather 128 environmental samples of water, soil, and air, along with samples of bird feces and feathers collected during the summer and winter of 2023. A total of 72 bird operational taxonomic units (OTUs) were identified. The results revealed variations in bird detection across different environmental samples, with air samples yielding 52 bird OTUs, water samples 29, and soil samples 23. Detected bird OTUs were notably higher in winter samples compared to summer. Additionally, the average number of bird OTUs detected in air samples during summer and winter was 14.9 and 10.1, respectively, significantly exceeding those found in the corresponding water and soil samples. The identification of bird feces and feather samples confirmed the presence of the identified bird species in the environmental samples. This study concludes that environmental DNA technology can serve as a valuable complementary method for monitoring bird diversity, with different environmental samples showing distinct preferences in bird detection.

ecology↗

bioRxiv2025

Impaired oxidative phosphorylation drives primary tumor escape and metastasis

Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.

cancer biology↗

bioRxiv2024

Phosphotyrosine Signal Profiling of Clinical CAR-T Reveals Tonic Signaling Associated with Therapeutic Efficacy

Chimeric Antigen Receptor T (CAR-T) therapies have revolutionized the treatment of cancers such as relapsed and refractory B cell malignancies. However, the precise therapeutic mechanism of CAR-T action remain to be elucidated. In this study, we systematically analyzed CAR signaling via phosphotyrosine (pTyr) proteomics in CAR-T cells from both clinical patients and healthy donors. We found that CAR-T products from clinical patients displayed heightened tyrosine phosphorylation, particularly in the JAK-STAT, MAPK and TCR signaling cascades. We also identified the significantly regulated pTyr sites in primary CAR-T cells under tonic signaling or upon stimulation by antigen-presenting CD19-K562 cells. Although both CD28{zeta} and 4-1BB{zeta} CAR-T cells exhibited comparable pTyr changes, CD28{zeta} CAR-T cells displayed a more pronounced activation in the TCR signaling pathway. Additionally, comparative analysis between clinical and primary CAR-T cells suggested that CAR-T products were subject to heightened tonic signaling, which may be related to therapeutic relapse. Our findings reveal the state of clinical CAR-T products and refine the CAR-T signal transduction network, providing comprehensive insights and informed guidance for CAR-T therapies.

immunology↗

bioRxiv2024

BC-Design: A Biochemistry-Aware Framework for High-Precision Inverse Protein Folding

Inverse protein design (IPD) extends the classical problem of inverse protein folding (IPF) by not only recovering a sequence compatible with a given backbone geometry but also generating a range of new sequences that satisfy the physicochemical constraints required for a stable fold with a specified (often designed) function. Recent progress has incorporated biochemical properties as discrete per-residue features, but such localized signals cannot represent the continuous hydrophobic and electrostatic environments that span protein surfaces and interior volumes. Here we introduce BC-DO_SCPLOWESIGNC_SCPLOW, a biochemistry-aware inverse design framework that integrates geometric structure with smoothly varying hydrophobicity and charge properties. The later are represented independent of residue coordinates, on compact point clouds sampled throughout protein surfaces and interiors. This formulation provides a natural spatial description of physicochemical environments and enriches structural cues without specifying amino-acid identities. On the CATH 4.2 benchmark, BC-DO_SCPLOWESIGNC_SCPLOW achieves 90% sequence recovery and generalizes robustly across protein lengths, contact-order regimes, and major fold classes. Masking experiments further demonstrate an interpretable fidelity-diversity control: full biochemical context yields high-fidelity reconstructions, whereas withholding information enables exploratory variant generation. Beyond diagnostic benchmarks, BC-DO_SCPLOWESIGNC_SCPLOW demonstrably improves functional design outcomes across diverse settings. It increases enzyme-substrate affinity, enhances peptide-receptor design accuracy, and achieves state-of-the-art recovery and structural fidelity in antibody loop (CDRH3) modeling. In these applications, the model not only reconstructs native-like sequences but also proposes plausible functional variants that preserve catalytic or binding geometry--such as generating CDRH3 loops that maintain antigen-contact configurations while offering new sequence solutions. These results show that integrating continuous physicochemical properties with structural geometry enables practical, function-oriented protein design, going beyond backbone-conditioned recovery.

bioinformatics↗

bioRxiv2024

Denoising complex-valued diffusion MR images using a two-step non-local principal component analysis approach

Purposeto propose a two-step non-local principal component analysis (PCA) method and demonstrate its utility for denoising diffusion tensor MRI (DTI) with a few diffusion directions. MethodsA two-step denoising pipeline was implemented to ensure accurate patch selection even with high noise levels and was coupled with data preprocessing for g-factor normalization and phase stabilization before data denoising with a non-local PCA algorithm. At the heart of our proposed pipeline was the use of a data-driven optimal shrinkage algorithm to manipulate the singular values in a way that would optimally estimate the noise-free signal. Our approachs denoising performances were evaluated using simulation and in-vivo human data experiments. The results were compared to those obtained with existing local-PCA-based methods. ResultsIn both simulation and human data experiments, our approach substantially enhanced image quality relative to the noisy counterpart, yielding improved performances for estimation of relevant DTI metrics. It also outperformed existing local-PCA-based methods in reducing noise while preserving anatomic details. It also led to improved whole-brain tractography relative to the noisy counterpart. ConclusionThe proposed denoising method has the utility for improving image quality for DTI with reduced diffusion directions and is believed to benefit many applications especially those aiming to achieve quality parametric mapping using only a few image volumes.

neuroscience↗

bioRxiv2024

Biotic resistance predictably shifts microbial invasion regimes

Invading new territory is a central aspect of the microbial lifestyle, allowing microbes to expand to remote locations and pathogens to spread and infect their hosts. However, invading microbes rarely find novel territories uninhabited. In such a scenario, resident microbes can interact with the newcomers and, in many cases, impede their invasion - an effect known as biotic resistance. Accordingly, invasions are shaped by the interplay between dispersal and resistance. However, these two factors are difficult to disentangle or manipulate in natural systems, making their interplay difficult to understand. To address this challenge, we tracked microbial invasions in the lab over space and time - first in a model system of two interacting microbes, then in a multi-strain system involving a pathogen invading resident communities. In the presence of biotic resistance, we observed three qualitatively different invasion regimes: consistent, pulsed, and pinned, where, in the third regime, strong biotic resistance stalled the invasion entirely despite ongoing invader dispersal. Surprisingly, these rich invasion dynamics could be qualitatively predicted with a simple, parameter-free framework that ignores individual species interactions, even for rather complex communities. Moreover, we showed that this simple framework could accurately predict simulated invasions from different mechanistic models, indicating its broad applicability. Our work offers a thorough understanding of how biotic resistance impacts invasions and introduces a predictive tool to identify invasion-resistant communities.

systems biology↗

bioRxiv2024

The first near-complete genome assembly of pig: enabling more accurate genetic research

Pigs are crucial sources of meat and protein, valuable animal models, and potential donors for xenotransplantation. However, the existing reference genome for pigs is incomplete, with thousands of segments and missing centromeres and telomeres, which limits our understanding of the important traits in these genomic regions. To address this issue, we present a near complete genome assembly for the Jinhua pig (JH-T2T), constructed using PacBio HiFi and ONT long reads. This assembly includes all 18 autosomes and the X and Y sex chromosomes, with only six gaps. It features annotations of 46.90% repetitive sequences, 35 telomeres, 17 centromeres, and 23,924 high-confident genes. Compared to the Sscrofa11.1, JH-T2T closes nearly all gaps, extends sequences by 177 Mb, predicts more intact telomeres and centromeres, and gains 799 more genes and loses 114 genes. Moreover, it enhances the mapping rate for both Western and Chinese local pigs, outperforming Sscrofa11.1 as a reference genome. Additionally, this comprehensive genome assembly will facilitate large-scale variant detection and enable the exploration of genes associated with pig domestication, such as GPAM, CYP2C18, LY9, ITLN2, and CHIA. Our findings represent a significant advancement in pig genomics, providing a robust resource that enhances genetic research, breeding programs, and biomedical applications.

genomics↗

bioRxiv2024

Accelerated multi-shell diffusion MRI with Gaussian process estimated reconstruction of multi-band imaging

PurposeThis work aims to propose a robust reconstruction method exploiting shared information across shells to increase the acquisition speed of multi-shell diffusion MRI, enabling rapid tissue microstructure mapping. Theory and MethodsLocal q-space points share similar information. Gaussian Process can exploit the q-space smoothness in a data-driven way and provide q-space signal estimation based on the signals from a q-space neighborhood. The Diffusion Acceleration with Gaussian process Estimated Reconstruction (DAGER) method uses the signal estimation from Gaussian process as a prior in a joint k-q reconstruction and improves image quality under high acceleration factors compared to conventional (k-only) reconstruction. In this work, we extend the DAGER method by introducing a multi-shell covariance function and correcting for Rician noise distribution in magnitude data when fitting the Gaussian process model. The method was evaluated with both simulation and in vivo data. ResultsSimulated and in-vivo results demonstrate that the proposed method can significantly improve the image quality of reconstructed dMRI data with high acceleration both in-plane and slice-wise, achieving a total acceleration factor of 12. The improvement of image quality allows more robust diffusion model fitting compared to conventional reconstruction methods, enabling advanced multi-shell diffusion analysis within much shorter scan time. ConclusionThe proposed method enables highly accelerated dMRI which can shorten the scan time of multi-shell dMRI without sacrificing quality compared to conventional practice. This may facilitate a wider application of advanced dMRI models in basic and clinical neuroscience.

bioengineering↗

bioRxiv2024

Gene encoding CC-NBS-LRR protein on rye chromosome 1RS confers wheat stripe rust resistance

Stripe rust, a globally widespread disease, stands as one of the most significant threats to wheat cultivation. The 1BL/1RS translocation, renowned for its robust resistance to both rust and powdery mildew, has historically played an important role in wheat breeding and production. The gene for resistance to stripe rust on the 1RS is known as Yr9 and plays an important role in the production of wheat, but over the course of long-term breeding had lost its resistance due to the evolution of stripe rust towards greater and greater virulence. In this paper, we cloned the stripe rust resistance gene, Yr9, from triticale by genetic mapping approach. The Yr9 encodes a typical nucleotide-binding leucine-rich repeat (NLR) protein. Both transgenic and overexpression of Yr9 in highly stripe rust susceptible wheat varieties conferred complete resistance to the stripe rust races CYR17 and partial resistance to the stripe rust races CYR32, CYR33, and CYR34. In addition, the Yr9 allele in the 1BL/1RS translocation line also showed the same level of resistance to stripe rust. Both two alleles loses resistance when deployed in the field or inoculated with mixed physiological races collected from the field. Our findings provide valuable insights for breeders to strategically incorporate disease resistance genes and provides a foundation for further understanding how pathogenic bacteria might evolve to evade recognition via NLR type proteins. SignificanceThe 1BL/1RS translocation between wheat and rye is the most successful case of exogenous gene application in plant genetic improvement and has been used in wheat breeding for over 50 years. Here we report the cloning of a stripe rust resistance gene Yr9 located on rye chromosome 1RS using a triticale population. The Yr9 encodes a coiled-coil nucleotide-binding site leucine-rich repeat (CC-NBS-LRR) protein that show complete resistance to the stripe rust races CYR17 and partial resistance to the stripe rust races CYR32, CYR33, and CYR34, albeit demonstrating susceptibility under field conditions. Our findings position Yr9 as an ideal candidate gene to study the mechanism of inactivation of disease resistance genes as a result of pathogen evolution.

genetics↗

bioRxiv2024

Environment-mediated interactions cause an externalized and collective memory in microbes

Microbes usually live in complex communities interacting with many other microbial species. These interactions determine who can persist in a community and how the overall community forms and functions. Microbes often exert interactions by chemically changing the environment, like taking up nutrients or producing toxins. These environmental changes can persist over time. We show here that such lasting environmental changes can cause a memory effect where current growth conditions alter interaction outcomes in the future. Importantly, this memory is only stored in the environment and not inside the bacterial cells. Only the collective effort of many bacteria can build up this memory, making it an emergent property of bacterial populations. This "population memory" can also impact the assembly of more complex communities and lead to different final communities depending on the systems past. Overall, we show that to understand interaction outcomes fully, we not only have to consider the interacting species and abiotic conditions but also the systems history.

systems biology↗

bioRxiv2024

Organoid Modeling and Single-Cell Profiling Uncover the Migration Mechanism of Smooth Muscle Cells in Moyamoya Disease

Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive occlusion of the intracranial arteries, resulting in severe ischemic or hemorrhagic stroke. The main characteristic of the affected vessels in MMD is arterial intimal thickening. However, there are no in vitro or in vivo models that can mimic its vascular characteristics. Moreover, the mechanisms underlying the intimal thickening remain unexplained. Here, we generated vascular organoids by differentiating human induced pluripotent stem cell derived from the peripheral blood of MMD patients, thereby creating an organoid model reflecting both the genetic background and characteristics of the affected vessels. Through single-cell sequencing, we found the increased vascular smooth muscle cell (VSMC) proportion and its functional abnormalities in MMD organoids. Proteomics and RNA sequencing identified abnormal TUBA4A and TUBB4B overexpression in both the organoids and patient serum. The following in vitro experiments demonstrated that TUBA4A and TUBB4B promote the contractile-to-synthetic phenotypic switching, migration and proliferation in VSMC. Further experiments identified the GJA1-mediated PI3K/AKT/KLF4 pathway as a key regulating pathway of these phenotypic changes in VSMCs. Our findings demonstrate that the abnormal expression of TUBA4A and TUBB4B in VSMC might be a significant contributor to the intimal thickening in the affected vessels of MMD.

cell biology↗

bioRxiv2024

Human-specific features of cerebellar astrocytes and Purkinje cells: an anatomical comparison with mice and macaques

Little is known about the morphological diversity and distribution of cerebellar astrocytes in the human brain and how or if these features differ from those of cerebellar astrocytes in species used to model human illnesses. To address this, we performed a comparative post-mortem examination of cerebellar astrocytes and Purkinje cells (PCs) in healthy humans, macaques, and mice using microscopy-based techniques. Visualizing with canonical astrocyte markers glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase-1 family member L1 (ALDH1L1), we mapped astrocytes within a complete cerebellar hemisphere. Astrocytes were observed to be differentially distributed across the cerebellar layers, displayed overall increases in area coverages with evolution, and showed features uniquely hominoid. Stereological quantifications in 3 functionally distinct cerebellar lobules demonstrated opposing trends for the canonical astrocyte markers across species with ALDH1L1+ astrocytes increasing with evolution and GFAP+ astrocytes decreasing. PC analyses revealed that while humans have the lowest PC densities, their cell body sizes were the largest with more ALDH1L1 immunoreactive astrocytes surrounding. Notably, the cognitive lobule crus I displayed the highest ratio of Bergmann glia to PC in all species. These findings align with the growing literature for astrocyte and PC heterogeneity and suggest cerebellar astrocyte and PC divergence both within and across species, possibly indicative of a role for these cells in higher-order cerebellar processing.

neuroscience↗