Biology subjects

Luo, J.

Publications and source records attributed to Luo, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Integrative genomic insights into parallel local adaptation to Danxia and Karst edaphic islands in the endangered tree Firmiana danxiaensis

Uncovering the genetic basis of local adaptation is a central goal in evolutionary biology. Edaphic islands, such as Karst (KL) and Danxia (DL) landforms, provide ideal natural laboratories for this endeavor. However, the mechanisms underlying parallel adaptation to contrasting edaphic extremes within a single species remain poorly understood. Firmiana danxiaensis, an endangered tree endemic to both KL and DL in the Nanling Mountains, offers a rare opportunity to address this question. We integrated a chromosome-level genome assembly, population genomic analysis of 225 individuals from 20 populations across its entire range, and genotype-environment association (GEA) with high-resolution soil and climate data. The relatively large genome of F. danxiaensis (1.51 Gb) reveals two ancient whole-genome duplications and a Quaternary burst of LTR retrotransposons, which, together with significant expanded drought-related transcription factor (TF) families, together constitute its genomic basis of adaptation. Population structure resolved four genetic lineages with distinct demography and inbreeding patterns. GEA identified stronger local adaptation in DL than KL, driven mainly by soil factors (e.g., cadmium, zinc), while climate variables (e.g., Bio9, Bio11) predominated in KL. Despite these divergent drivers, drought stress and elevated metal ion acted as major selective pressures in both landforms. Furthermore, six key TFs (e.g., NAC090, bHLH42, MAPKKK20) under both local adaptation and positive selection in DL are involved in drought response and metal ion binding, facilitating survival in stressful habitats. Our findings provide novel insights into parallel local adaptation to contrasting edaphic islands and offer concrete genomic guidance for the conservation of F. danxiaensis. Significance statementThe genetic basis of parallel local adaptation to contrasting environments remains unclear. Using the endangered tree Firmiana danxiaensis, we uncover genomic mechanisms enabling its adaptation to both Karst and Danxia edaphic islands. We demonstrate that adaptation is primarily driven by soil factors in Danxia and climate in Karst, generating divergent genomic signatures yet converge on drought response. These findings establish a framework for understanding parallel local adaptation and offer concrete genomic guidance for conservation.

evolutionary biology↗

bioRxiv2025

Cohesin Acetylation and ATPase Activity Control Cohesion and Loop Architecture through Distinct Mechanisms

Cohesin is a conserved protein complex that mediates sister chromatid cohesion, chromosome condensation, gene regulation, and DNA repair. These processes rely on cohesins ability to tether sister chromatids and form chromatin loops, which depend on cohesins ATPase activity and Eco1-mediated acetylation of two lysine residues (K112 and K113 in budding yeast) in its Smc3 subunit. How cohesins ATPase activity and acetylation integrate to control cohesin functions remains poorly understood. Here, we analyzed chromatin architecture in yeast mutants with altered cohesin acetylation and/or ATPase activity. We find that acetylation of either K112 or K113 is sufficient to produce a wild-type chromosome structure with loops positioned at cohesin-associated regions (CARs), whereas loss of acetylation at both residues abolishes positioned loops, indicating that acetylation at either lysine alone can maintain wild-type chromatin architecture. We further show that a cohesin acetylation mutant, despite being defective in sister-chromatid tethering and thus failing to establish cohesion, still forms wild-type-like loops, while cohesion-competent mutants lack positioned loops. These results suggest that the activities required for cohesion and loop formation are mechanistically separable, arguing against passive loop capture. Moreover, a mutant with reduced ATPase activity showed a loop profile similar to wild type, indicating that cohesin with lower ATPase activity can still form wild-type chromatin architecture. By contrast, hyper-ATPase mutants accumulate positioned loops, suggesting that increasing ATPase activity can enhance loop processivity. Together, our findings support a multilayered regulatory model in which acetylation fine-tunes ATPase output and cohesin functions to shape genome architecture.

genetics↗

bioRxiv2025

Leonardo: a toolset to correct sample-induced artifacts in light sheet microscopy images

Selective plane illumination microscopy (SPIM, also known as light sheet fluorescence microscopy) is the method of choice for studying morphogenesis and function in biological specimens over extended periods, as it permits gentle and rapid volumetric imaging. In inhomogeneous samples, however, sample-induced artifacts, including light absorption, scattering, and refraction, can impact the image quality, particularly as the focal plane gets deeper into the sample. Here, we present Leonardo, the first toolbox designed to address the major sample-induced artifacts by using two modules: (1) DeStripe removes stripe artifacts in SPIM caused by light absorption while preserving fine sample structures; (2) Fuse reconstructs a single high-quality image from dualsided illumination and/or dual-sided detection, while eliminating blur and optical distortions caused by light scattering and refraction. The efficacy of Leonardo is validated on a wide range of biological samples, from minimally invasive experiments on sensitive specimens (translucent embryonic and optically opaque larval zebrafish) to cleared mouse samples up to two centimeters in size. We provide model code and a Napari-based graphical user interface, enabling the SPIM community to easily apply Leonardo to advance light sheet imaging of inhomogeneous and complex specimens.

bioinformatics↗

bioRxiv2025

Histology-informed spatial domain identification through multi-view graph convolutional networks

Identifying spatial domains is crucial in spatial transcriptomics, yet effectively integrating gene expression, spatial location, and histology remains challenging. We present STESH, a Spatial Transcriptomics clustering method that combines Expression, Spatial information and Histology. STESH extracts histological features using a convolutional neural network and generates expression, histology, spatial, and collaborative convolution modules for a multi-view graph convolutional network with a decoder and attention mechanism. We evaluated STESH on multiple tissue types and technology platforms. STESH consistently outperformed ten state-of-the-art methods, achieving superior clustering accuracy with the highest scores in adjusted Rand index, normalized mutual information, and Fowlkes-Mallows index.

bioinformatics↗

bioRxiv2025

Response expectations shape serial dependence and stimulus processing

Perceptual decisions are biased by recent history, yet the balance between attractive and repulsive effects varies across contexts. Here, we tested whether trial-by-trial response expectations shape the direction of history biases in serial dependence during orientation reproduction. Behaviorally, we found that no-response trials--especially when rare--reduced attractive biases and enhanced repulsive biases. EEG results revealed stronger evoked responses and amplified neural representations for stimuli following no-response trials. Together, these findings suggest that interrupting the perception-action cycle fosters a state of re-engagement with current input and disengagement from past stimuli, indicating that serial dependence is a flexible process dynamically modulated by task expectations and transient shifts in sensory processing.

neuroscience↗

bioRxiv2025

Predicting SARS-CoV-2 evolution dynamics with spatiotemporal resolution by DMS-empowered protein language model

Early identification of emerging dominant SARS-CoV-2 variants is essential for effective pandemic preparedness, yet existing methodologies face significant limitations. Experimental characterizations are costly and not feasible for real-time surveillance, whereas existing computational approaches cannot achieve satisfactory precision in predicting future dominant lineages and fail to capture the spatiotemporal dynamics of fitness under evolving host immune pressures. Here, we introduce DeepCoV (DMS-Empowered Evolution Prediction of CoronaVirus), a deep-learning framework for the dynamic identification of novel variants with high potential to become prevelent. It integrates deep mutational scanning (DMS)-derived mutation phenotypes with epidemiological surveillence data reflecting historical viral evolution and the dynamic fitness landscape. DeepCoV accurately forecasted the dominance of recently circulating lineages a month in advance, achieving a 90% reduction in false discovery rate while capturing temporal and geographic dynamics of variant spread and reconstructing their regional prevalence trajectories. Moreover, DeepCoV identified mutational hotspots of Omicron-derived backbones in silico, revealing convergent evolution trends. This scalable solution enables timely identification of immune-evasive variants and prospective alert of critical mutations, providing actionable insights for vaccine updates and pandemic surveillance.

microbiology↗

bioRxiv2025

Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease

Alzheimers disease (AD) is the most common neurodegenerative disorder, yet the molecular mechanisms underlying its region- and cell-type-specific pathogenesis remain poorly defined. Here, we generated a large-scale, single-cell multi-omic atlas--integrating DNA methylation and 3D genome architecture--from postmortem brain tissue of matched AD patients and cognitively normal controls. Samples were collected from three brain regions with distinct vulnerability to AD pathology: the temporal cortex (TC), primary visual cortex (VC), and prefrontal cortex (PFC). Our dataset comprises over 230,000 individual cells, spanning major neuronal and glial populations, and provides a high-resolution view of multi-layer epigenomic regulation. We identified widespread AD-associated DNA methylation changes and marked reorganization of 3D genome structure, including alterations in A/B compartments, topologically associating domains (TADs), and chromatin loops. These changes are strongly region-specific: TC displays pronounced hypermethylation, transcriptional downregulation, and elevated boundary density, whereas VC shows opposing trends and PFC an intermediate profile. We further uncovered previously unrecognized AD-associated glial and neuronal states defined by coordinated epigenomic dysregulation and recurrent genomic deletions, particularly near telomeric regions. This region-resolved, single-cell multi-omic atlas reveals divergent epigenomic trajectories across brain regions and cell types in AD, offering new mechanistic insights and a framework for targeted therapeutic strategies.

genomics↗

bioRxiv2025

Hepatic cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): Topological determinants and cellular partnerships that dictate the preferential P450 proteolytic sorting into macroautophagy rather than UPS.

Many N-terminally endoplasmic reticulum (ER)-anchored cytochrome P450 proteins (P450s) turn over proteolytically via ER-associated degradation (ERAD), others via ER-to-lysosomal-associated degradation (ERLAD), and yet others via both pathways. What precisely dictates their differential proteolytic turnover is unknown. Herein, we employed rabbit liver CYPs 1A1 and 1A2, which reportedly reside in liquid-disorded (ld)- and detergent-resistant, liquid-ordered (lo)-ER-microdomains, respectively, governed by their specific N-terminal (NT) signal-anchor (SA) subdomains. We now report that this precise SA-dependent ER-topology not only determines the proclivity of CYP1A1 towards ERAD and CYP1A2 towards ERLAD, but also their differential lifespans. We further document that the detergent-resistant lo-ER-membranes (DRMs) are morphologically quite similar to mitochondria-associated ER-membranes (MAMs), documented cellular platforms for autophagic-initiation complexes. DRMs and MAMs, composed of saturated fatty-acids, glycosphingolipids and cholesterol, harbor many common morphological markers including the ER-specific prohibitin, erlin-1. Herein employing SURF, a split fluorogenic bifunctional complementation assay, we show that intracellularly, erlin-1 and CYP1A2 interact closely via their ER NT-SAs. siRNA-knockdown (KD) of erlin-1 in HepG2-cells, not only relocated CYP1A2 from DRMs to non-DRMs, but also impaired its ERLAD, resulting in insoluble cellular CYP1A2 aggregates. Upon erlin-1 KD, CYP1A2 ERLAD could be rescued by co-expression of a siRNA-resistant intact erlin-1 or just its NT-1-30 residue SA-domain. Our findings are the first to reveal that the CYP1A2 lifespan and preferential proclivity towards ERLAD is determined by its close association with erlin-1 within DRMs/MAMs. As proof of concept, we document that the ERLAD-proclivity of CYP2B1 is also similarly dependent upon erlin-1-DRM-association. SIGNIFICANCE STATEMENTThe endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) incur ER-associated degradation (ERAD) and/or ER-to-lysosomal-associated degradation (ERLAD). What determines their preferential proteolytic turnover is unknown. Here, employing P450s CYP1A1 and CYP1A2 that reside in their N-terminal signal anchor-determined liquid-disordered (ld)- and detergent-resistant, liquid-ordered (lo)-ER-microdomains, respectively, we documented that in HepG2-cells these ER-microdomains determine the CYP1A proteolytic preferences for ERAD vs ERLAD as well as their lifespans. More importantly, we discovered that its intimate interaction with the ER-specific prohibitin erlin-1 colocalized in these lo-ER-microdomains, specifically dictates CYP1A2s ERLAD-preference. Accordingly, siRNA-elicited erlin-1-knockdown disrupted CYP1A2-ERLAD, which was rescued upon coexpression of either a siRNA-resistant erlin-1 or just its N-terminal 1-30 residues. As proof of concept, we document similar characteristics for CYP2B1, another ERLAD-targeted P450.

cell biology↗

bioRxiv2025

Prokineticin-2 Upregulates GDNF in Astrocytes and Pharmacological Modulation of PK2 Receptors offers Neuroprotection in Experimental Models of Parkinson's Disease

Despite a wealth of preclinical studies establishing neuroprotective and neurorestorative properties of glial cell-line-derived neurotrophic factor (GDNF) in animal models of Parkinsons disease (PD), clinical trials utilizing direct intracranial infusion of GDNF protein, or adeno-associated virus (AAV)-mediated GDNF gene transfer has not achieved the desired efficacy, largely due to challenges in delivery methods. Given GDNFs strong potential for neuroprotection, alternative strategies to elevate its expression by beyond invasive injection or genetic manipulation remain a promising therapeutic avenue for PD. We previously reported that prokineticin signaling provides a compensatory protective response against dopaminergic neuronal degeneration in cell and animal models of PD. Herein, we report a novel finding that PK2 regulates GDNF gene expression in astrocytes, suggesting that PK2 signaling can be harnessed for neuroprotection in PD. Treatment of cultured astrocytes with the PK2 protein, PK2 gene overexpression or prokineticin receptor 1 (PKR1) agonist IS20 significantly induced the GDNF gene expression and the protein secretion, resulting in enhanced dopaminergic cell survival in cell culture models of PD. Importantly, systemic administration of IS20 through intraperitoneal or intranasal routes elevated GDNF levels in the mouse brain, including the nigrostriatal system. Furthermore, IS20 treatment conferred significant neuroprotective effects in both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and MitoPark transgenic mouse models of PD. Collectively, our translational findings suggest that pharmacological modulation PK2 signaling may unlock the full clinical benefit of GDNF, offering a novel and non-invasive therapeutic strategy for Parkinsons disease.

pharmacology and toxicology↗

bioRxiv2025

Resolving the estrogen paradox in hereditary retinal degeneration: Esr1 activation suppresses Tnf-α signaling as a photoreceptor self-protection mechanism

Retinitis pigmentosa (RP) is an inherited retinal degenerative disorder characterized by progressive photoreceptor loss and irreversible blindness. Increasing evidence implicates neuroinflammation as a contributor to photoreceptor degeneration extending beyond the initial genetic insult. Although estrogen has been reported to exert anti-inflammatory effects in the central nervous system, its role in RP remains controversial, with some studies suggesting a paradoxical exacerbation of retinal pathology. To address this discrepancy, we identify estrogen receptor alpha (Esr1) as a central immunoregulatory hub in RP. Transcriptomic analyses of rd1 and rd10 revealed upregulation of estrogen-responsive and inflammatory pathways, with Esr1 expression markedly elevated during degeneration. TUNEL assays demonstrated that systemic estradiol (E2) exerted divergent effects, protective in rd1 yet deleterious in rd10, whereas selective pharmacological activation of Esr1 with propyl pyrazole triol (PPT) consistently reduced photoreceptor death, preserved dark-adapted ERG responses, and downregulated inflammatory mediators including Tnf-, Cx3cl1/Cx3cr1, Cd68, and Iba1. Mechanistically, Esr1 activation repressed microglial Tnf transcription and disrupted a self-sustaining Cx3cl1/Cx3cr1-Tnf- signaling loop driving microglial recruitment, activation and neurotoxicity in the outer nuclear layer (ONL). Targeted interventions confirmed tumor necrosis factor receptor 1 (Tnfr1) as the principal mediator of Tnf-induced photoreceptor death: selective inhibition with R7050 conferred superior protection compared with broad-spectrum Tnf- inhibitors (etanercept, infliximab). Cx3cr1 blockade likewise suppressed microglial activation and improved visual outcomes. Collectively, our findings establish Esr1 activation as not merely an external intervention but the amplification of an intrinsic self-protective program, positioning Esr1, Tnfr1, and Cx3cr1 as actionable therapeutic targets to suppress neuroinflammation and preserve vision in RP and related retinal disorders.

neuroscience↗

bioRxiv2025

Shaker it OFF: Biophysical Characterization of an Inactivating Potassium Conductance Mediating Object Segmentation in a Collision-Detecting Neuron

Homologous ion channels are expressed in sensory neurons across species where they shape responses to varied sensory stimuli, on a wide range of timescales. In grasshoppers, visual detection of looming stimuli which simulate an approaching predator involves the sub-cellular expression pattern of a newly characterized Shaker channel in a single identified neuron, discovered using a newly sequenced genome and single cell RNA sequencing. This channel shapes selectivity for approaching threats and was characterized with electrophysiological recordings, RNA interference, pharmacology and biophysical compartmental simulations. Our results explain how a slowly activating and inactivating potassium conductance common in neuronal dendrites contributes to visual object segmentation and implements a complex neural computation within a single neuron.

neuroscience↗

bioRxiv2025

To jump or not to jump: Comparing effects of phenotypic plasticity on the visual responses and escape behavior of locusts and grasshoppers

Locusts exhibit remarkable phenotypic plasticity changing their appearance and behavior from solitary grasshoppers to gregarious locusts when population density increases. These changes include morphological differences in the size and shape of brain regions, but little is known about plasticity within individual neurons and alterations in behavior not directly related to aggregation or swarming. We examined looming escape behavior and the properties of a well-studied collision-detection neuron in gregarious and solitarious animals of three closely related species, the desert locust (Schistocerca gregaria), the Central American locust (S. piceifrons) and the American bird grasshopper (S. americana). For this neuron, the lobula giant movement detector (LGMD), we examined dendritic morphology, membrane properties, gene expression, and looming responses. Gregarious animals reliably jumped in response to looming stimuli, but surprisingly solitarious desert locusts did not produce escape jumps. These solitarious animals also had smaller LGMD dendrites. This is the first study done on three different species of grasshoppers to observe the effects of phenotypic plasticity on the jump escape behavior, physiology and transcriptomics of these animals. Surprisingly, there were little differences in these properties between the two phases except for behavior. For all the three species, gregarious animals jumped more than solitarious animals, but no significant differences were found between the two phases of animals in the electrophysiological and transcriptomics studies. Our results suggest that phase change impacts mainly the motor system and that the physiological properties of motor neurons need to be characterized to understand fully the variation in jump escape behavior across phases. New & Noteworthy (74 words): Swarming is observed in some grasshopper species, called locusts. We compared jump escape behavior between gregarious and solitarious grasshoppers and locusts, as well as LGMD responses to looming stimuli, and analyzed the morphological differences in this neuron. This study provides insights into the effects of phase change on the visual system of locusts and grasshoppers as it relates to looming-evoked jump escape behavior. In this context, our results suggest that phenotypic plasticity mainly impacts the motor system.

neuroscience↗

bioRxiv2025

The Nox2 NADPH oxidase regulates neutrophilic inflammation in the oral cavity

The leukocyte NADPH oxidase 2 (NOX2) is an important regulator of inflammatory responses, independent of its antimicrobial activity. Inactivating mutations in NOX2 cause chronic granulomatous disease (CGD), a severe immunodeficiency associated with recurrent infections and dysregulated neutrophilic inflammation. Recurrent oral ulcers, stomatitis, gingivitis, and other inflammatory issues affecting the oral mucosa have been observed in patients with CGD; however, the underlying mechanisms are not known. Here, we present evidence that the extensive inflammatory destruction of oral mucosal tissues observed in Nox2-deficient or CybbKOmice was not caused by impaired antimicrobial surveillance against oral pathobionts but instead resulted from a cell-intrinsic dysregulation of neutrophil inflammatory responses. Transcriptional and cellular profiling of oral tissues isolated from wild-type and CybbKO mice showed a dominant neutrophil signature, which was accompanied by a significant upregulation of several bone-resorbing, tissue-degrading inflammatory cytokines and a reduced expression of nuclear factor erythroid 2-related factor 2 (Nrf2) regulated genes. Mechanistically, hyperinflammatory responses were mitigated by restoring Nrf2 transcriptional activity using a synthetic agonist. Thus, our studies show that Nox2 oxidase and its derived reactive oxygen species are crucial for balanced recruitment and cell-intrinsic regulation of neutrophil inflammatory responses within oral tissues in an Nrf2-dependent manner.

immunology↗

bioRxiv2025

Protein-Driven Copper Redox Regulation: Uncovering the Role of Disulphide Bonds and Allosteric Modulation

Copper plays essential roles in enzymatic activity, redox reactions, and cellular signalling, but becomes toxic when redox homeostasis is disrupted. While Cu(II) reduction is commonly attributed to unfolded or amyloid proteins, here we show that the well-folded plasma protein human serum albumin (HSA) intrinsically reduces Cu(II) to Cu(I) in the absence of external reductants. Using X-ray absorption spectroscopy (XAS), small-angle X-ray scattering (SAXS), circular dichroism (CD) and computational modelling (QM/MM and DFT), we identify a redox mechanism involving the disulphide bond Cys392-Cys438 in domain III of HSA. Cu binding at the high-affinity ATCUN motif triggers conformational changes that expose this disulphide bond, enabling thiol-mediated electron transfer and Cu(I) formation. Chelation with tetrathiomolybdate (TTM) impairs this reduction by restricting access to the reactive disulphide site. Comparative analysis with other globular proteins reveals that Cu reduction requires both accessible disulphide motifs and a native folded structure. Simulations and spectroscopy of SOD1 confirm that disulphide cleavage enhances Cu-thiolate interaction, supporting a generalizable two-site redox mechanism. These findings reveal a previously unrecognized mode of protein-mediated copper reduction and suggest broader physiological roles for disulphide-regulated redox switching in metal homeostasis.

biochemistry↗

bioRxiv2025

Design of an ultrabright biosensor for dynamic imaging of kinase activity in cells

Protein kinases regulate almost every major signaling pathway. Visualizing spatiotemporal dynamics of kinase activity is thus essential to understand cell signaling. Here we report a de novo-designed activity reporter of kinase, dubbed NOVARK, which contains a single polypeptide chain with multiple modular motifs that act as specific kinase substrates and reporters. NOVARK undergoes phosphorylation-induced higher order-assembly, which are detectable as ultrabright GFP droplets with a greater dynamic range than existing Forster resonance energy transfer-based kinase reporters. We designed versions of NOVARK that rapidly and reversibly report intracellular activity of protein kinase A, C, and ERK following stimulation/inhibition by upstream GPCR agonists. Our work provides a generalizable platform that enables the design of ultrabright biosensors for illuminating dynamic architecture of kinase signaling.

bioengineering↗

bioRxiv2025

Gene model for the ortholog of Akt in Drosophila elegans

Gene model for the ortholog of Akt kinase (Akt) in the April 2013 (BCM-HGSC/Dele_2.0) Genome Assembly (GenBank Accession: GCA_000224195.2) of Drosophila elegans. This ortholog was characterized as part of a developing dataset to study the evolution of the Insulin/insulin-like growth factor signaling pathway (IIS) across the genus Drosophila using the Genomics Education Partnership gene annotation protocol for Course-based Undergraduate Research Experiences.

genomics↗

bioRxiv2025

Platelets drive immune suppression and glioblastoma growth in a sex-dependent manner via PAR4 signaling

Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8 T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor {beta} (ER{beta})--a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8 T cell function, and depletion of CD8 T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

cancer biology↗

bioRxiv2025

A Core Pattern of Cerebellar and Brainstem Degeneration and Reduced Cerebrocerebellar Structural Covariance in Spinocerebellar Ataxia Type 3 (SCA3): MRI Volumetrics from ENIGMA-Ataxia

ObjectiveSpinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease. Here, we profile the spatial spread of atrophy across the whole brain, determine whether brain degeneration preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral anatomical changes. MethodsWhole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to investigate disease progression, with cerebellar GM atrophy mapped onto a task-based functional atlas. Volume was correlated with disease duration and intensity. Cerebrocerebellar volumetric covariance was assessed to determine whether atrophy was coupled between infra- and supratentorial regions. ResultsThe pattern of atrophy is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy was found in the pons, cerebellar WM, and cerebellar peduncles; correlations with disease severity and duration were also strongest in these regions. Cerebellar GM atrophy was greatest in functional regions associated with motor execution and planning, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages. Reduced cerebrocerebellar structural covariance is observed in SCA3 participants versus controls. InterpretationWhile cerebellar and brainstem atrophy become more severe, the pattern of atrophy remains largely consistent as SCA3 progresses. Cerebellar GM degeneration occurs in regions associated with motor, cognitive, and affective control, in line with clinical presentation. Cerebellar atrophy is not directly mirrored by cerebral changes.

neuroscience↗