Biology subjects

Lebrun, L.

Publications and source records attributed to Lebrun, L..

10 recordsLinked to original sources

bioRxiv2026

Behavioral Markers of Essential Tremor Correlate with Distributed Alteration of Brain Functional Connectivity

Essential Tremor (ET) is a common motor disorder characterized by involuntary oscillations of the upper limbs during voluntary movement. Although increasing evidence implicates dysfunction of the cerebello-thalamo-cortical pathway, ET remains a diagnosis of exclusion, as no definitive biological marker currently exists. To better characterize ET, we recently hypothesized that impaired compensation of sensorimotor delays within the long-latency feedback pathways may generate the tremor-like oscillations observed in ET. This theory suggests that the mean spectral amplitude (MSA), derived from limb kinematics, may serve as a potential marker of ET. Here we investigated the relationship between MSA, standard clinical assessment (Fahn Tolosa Marin Tremor Rating Scale; FTM-TRS), and brain connectivity derived from resting state functional magnetic resonance imaging (rs-fMRI). Using seed-based analyses, we replicated previous findings of reduced functional connectivity between the dentate nucleus and components of the cerebello-thalamo-cortical pathway in ET patients compared with neurologically intact (NI) age-matched participants. Graph-theoretical analyses of whole-brain functional networks revealed distributed alterations in network topology across motor-related cortical and subcortical regions. Several graph metrics correlated with FTM-TRS scores and/or MSA, particularly within motor-related cortical and subcortical circuits, including the thalamus, basal ganglia, and cerebellum in ET. These findings indicate that ET is characterized by distributed alterations in functional brain networks beyond reduced connectivity of dentate nucleus and highlights MSA as a candidate quantitative marker linking altered brain connectivity to sensorimotor delay-driven tremor oscillations.

neuroscience↗

bioRxiv2026

Reduced tubulin polyglutamylation perturbs neuronal function and causes late-onset neurodegeneration

Microtubules are essential for neuronal functions and are involved in many neurodegenerative disorders. A posttranslational modification (PTM) of neuronal microtubules, polyglutamylation, was shown to control cargo transport, Tau protein binding to microtubules and to induce early-onset neurodegeneration when exceeding physiological levels. To determine the physiological importance of this PTM, we characterised mouse models with reduced polyglutamylation. We demonstrate that these mice develop late-onset atrophy of the olfactory bulb and frontal cortex, progressively reduced dendritic spine density, and deficits in olfaction, memory, and cognitive control. This indicates an important role of polyglutamylation in neuronal function. To test whether the observed defects are linked to neurodegeneration, we combined mice with reduced polyglutamylation with a transgenic model for tauopathy. Strikingly, reduced polyglutamylation accelerated the premature demise of mice transgenic for human Tau carrying the P301S mutation. Our work thus reveals key roles of microtubule polyglutamylation in neuronal function with implications for late-onset neurodegeneration linked to Tau pathology.

neuroscience↗

bioRxiv2026

Integrating coastal microbiome observations for human, oyster and environmental protection

The Reseau dObservatoires de Microbiologie Environnementale integree (ROME) was a pilot study conducted in France from September 2020 to August 2023 aiming to establish a network of eDNA-based observatories across four estuarine ecosystems associated with oyster farming: the Bay of Veys (Normandy), the Bay of Brest (Brittany), Marennes-Oleron (Nouvelle-Aquitaine), and the Thau Lagoon (Occitania). Within a One Health framework, the study assessed the influence of river inputs on estuarine microbiome structuring and the emergence of microbiological hazards affecting human, aquaculture, and ecosystem health. Over 2,000 samples were collected during the study, including biweekly surface water and monthly adult oyster samples. Environmental nucleic acids were analysed using metabarcoding (bacterial and protist communities) and metagenomics (human RNA viruses). The coastal microbiome, including pathogenic and harmful taxa relevant to humans and aquatic invertebrates, was characterized. River influence on microbial community composition was examined through spatial comparisons of stations exposed to varying levels of freshwater runoff, while oysters acted as bio-integrators of local microbial diversity. Results revealed coherent coastal-to-offshore microbiome structuring across all ecosystems, with local variations linked to riverine inputs. eDNA metabarcoding allowed to detect a wide range of prokaryotic and eukaryotic pathogens, as well as harmful algal bloom (HAB) genera, several not captured by conventional monitoring. These findings demonstrate the potential of the ROME eDNA observatory network for high-resolution, integrative surveillance of microbial biodiversity and early detection of biological risks in estuarine environments.

genomics↗

bioRxiv2026

An atlas of human histological diversity

Descriptions of tissues by histopathologists rest on verbal statements limited by quantitative inaccuracies and personal cognitive biases. Here we propose an unsupervised computational framework that transposes to histology the concepts and methods of RNA-seq gene expression analysis, setting histology on an unbiased quantitative ground. Leveraging this framework and the GTEx dataset, we built an atlas surveying the histological diversity of 40 organs from 946 non-diseased individuals and documenting 11,125,747 associations between 2,560 morphemes--the histological analogs of genes in our framework--and 9 layers of patho-clinical and multi-omic molecular data, providing a rich context to interpret histology. In contrast with the ideally healthy normal specimens depicted in histology textbooks, the atlas reveals the influence of age, sex, genetics and sub-clinical pathologies on tissue structures. For example, we report that female eccrine sweat glands are surrounded by more adipocytes than their male counterparts, and that distinct calcification-associated aorta morphemes are driven by either smoking or genetic polymorphisms. Cross-organ analyses also delineate the systemic histological impact of diabetes and other conditions and establish the power of blood gene expression to predict disease-related morphemes. The atlas is released as an interactive web resource aimed at researchers.

pathology↗

bioRxiv2025

TTLL6-mediated Polyglutamylation of PurA Maintains Colonic Crypt Integrity

The tubulin tyrosine ligase-like (TTLL) family comprises enzymes catalyzing posttranslational modifications of tubulin, including glutamylation and glycylation. We previously described a critical role for the monoglycylase TTLL3 in colon. Here, we identified TTLL6 as the predominant polyglutamylase in the colon, specifically expressed in epithelial cells of distal and transverse segments. TTLL6 expression decreases during CRC progression, correlating with poor patient prognosis. Deletion of Ttll6 in mice resulted in elongated colonic crypts, expansion of stem and transit-amplifying compartments, and increased numbers of differentiated epithelial cells. Moreover, Ttll6-deficient mice showed an elevated susceptibility to chemically induced colon carcinogenesis. Notably, we identified the nucleic acid-binding protein PurA as a novel TTLL6 substrate with both proteins mutually required for nuclear localization. Consistently, both nuclear polyglutamylation and PurA were present in the bottom compartment of control colons, but reduced in Ttll6-deficient colons. These findings reveal a TTLL6-PurA axis being critical in maintaining colonic homeostasis.

cell biology↗

bioRxiv2025

Interindividual variations in peak alpha frequency do not predict the magnitude or extent of secondary hyperalgesia induced by high-frequency stimulation

BackgroundPrevious studies have shown an association between interindividual variations in the frequency of alpha-band EEG oscillations such as estimates of peak alpha frequency (PAF) and pain sensitivity. Whether differences in PAF also influence the susceptibility to develop central sensitization (CS) is unknown. ObjectiveThis study aimed to determine if the PAF of vision- and sensorimotor-related alpha-band activity is associated with the magnitude and extent of secondary mechanical hyperalgesia induced by high-frequency stimulation (HFS) of the skin, a surrogate marker of CS. MethodsThe EEG was recorded in 32 healthy participants at rest during eyes open and eyes closed conditions, and during bilateral finger movements. Two methods were used to isolate vision- and sensorimotor-related alpha-band activity based on sensitivity to eye closure and movement: one based on an independent component analysis, the other on spectral subtraction. PAF was assessed using a center-of-gravity approach or the Fitting Oscillations and One-Over-F (FOOOF) method, accounting for the aperiodic EEG component. HFS was applied to the right forearm, and pinprick sensitivity was assessed at both forearms, before and 40 minutes after HFS. ResultsNeither sensorimotor-nor vision-related PAF were significantly correlated with the magnitude or extent of HFS-induced secondary hyperalgesia. Interestingly, at the non-sensitized forearm, participants with a higher vision-related PAF exhibited greater habituation to pinprick stimuli, suggesting that variations in PAF may relate to variations in sensory habituation. ConclusionInterindividual variations of PAF were not significantly associated with the susceptibility to develop HFS-induced secondary hyperalgesia. New and NoteworthyUsing several methods to estimate vision- and sensorimotor-related peak alpha frequency (PAF) in the EEG frequency spectrum, we found no significant association between interindividual variations in PAF and the susceptibility to develop secondary hyperalgesia following high-frequency stimulation (HFS) of the skin in healthy participants.

neuroscience↗

bioRxiv2024

Glutamylation imbalance leads to photoreceptor degeneration

The stereotypic structure of microtubules, assembled from conserved /{beta}-tubulin dimers is subject to a complex diversity of Post-translational Modifications (PTMs). PTMs are predicted to fine-tune microtubule properties and interactions with other proteins, thus allowing microtubules to perform specific functions. Cilia accumulate several types of tubulin PTMs, such as polyglutamylation, polyglycylation, detyrosination and acetylation, whose functions are not yet fully understood. Recently, mutations of AGBL5, coding for the deglutamylating enzyme CCP5, have been associated to retinitis pigmentosa, suggesting that perturbation of polyglutamylation leads to the degeneration of photoreceptor cells. However, the molecular mechanisms underlying this degeneration remain unknown. Here, using super-resolution Ultrastructure Expansion Microscopy in mouse and human photoreceptor cells, we found that most tubulin PTMs are accumulated at the level of the connecting cilium, a structure linking the outer and inner segments of photoreceptor cells. Using mouse models with increased glutamylation (Ccp5-/- and Ccp1-/-), or loss of tubulin acetylation (Atat1-/-), we demonstrated that aberrant glutamylation, but not loss of acetylation, resulted in perturbed molecular architecture of the outer segment, with the loss of the bulge region and destabilization of the distal axoneme. Concurrently, we observed a substantial impairment in tubulin glycylation and intraflagellar transport. Altogether our results indicate that glutamylation plays a crucial role in the maintenance of the molecular architecture of the outer segment and point to tubulin PTM imbalance as possible culprit in retinal degeneration.

cell biology↗

bioRxiv2024

Erroneous compensation for long-latency feedback delays as origin of Essential Tremor

Essential tremor (ET), a movement disorder characterized by involuntary oscillations of the limbs during movement, remains to date not well understood. It has been recently suggested that the tremor originates from impaired delay compensation, affecting movement representation and online control. Here we tested this hypothesis directly with ET patients (N=24) and neurologically intact (NI) volunteers (N=28) in an upper limb postural perturbation task. After maintaining their hand in a visual target, participants experienced perturbations of unpredictable direction and magnitude, and were instructed to counter the perturbation and steer their hand back to the starting position. In comparison with NI volunteers, ET patients early muscular responses (Short and Long-Latency Responses, 20-50 ms and 50-100 ms respectively) were preserved or even slightly increased. However, they exhibited perturbation-dependent deficits when stopping and stabilizing their hand in the final target supporting the hypothesis that the tremor was generated by the feedback controller. We show in a computational model that errors in delay compensation accumulating over time produced the same small increase in initial feedback response followed by oscillations that scaled with the perturbation magnitude as observed in ET population. Our experimental results therefore validate the computational hypothesis that inaccurate delay compensation in long-latency pathways could be the origin of the tremor. Significance StatementEssential Tremor origin remains poorly understood. In the present study, we focused on motor impairments associated with feedback control. Following a mechanical perturbation applied to their arm, patients short and initial long-latency stretch responses were preserved. However, we observed clear impairments during the stabilization phase that scaled with the perturbation magnitude. These results were reproduced in a computational model where delay compensation was inaccurate, suggesting that the origin of the tremor may lie in an underestimation of the delays impacting the internal monitoring of the motor commands. Conflict of interestThe authors declare no competing financial interests.

neuroscience↗

bioRxiv2023

Impairments of motor adaptation in Essential Tremor are linked to movement execution

0.Essential tremor (ET) is a neurological disorder characterized by involuntary oscillations of the limbs. Previous studies have hypothesized that ET was a cerebellar disorder and reported impairments in motor adaptation. However, recent advances have highlighted that motor adaptation involved several components linked to anticipation and control, all dependent on cerebellum, and the specific alteration of adaptation of ET has not been identified. To address this question we investigated behavioural markers of adaptation in ET patients (n=20) and age-matched healthy volunteers (n=20) in saccadic and upper limb adaptation tasks, probing compensation for target jumps and for velocity-dependent force fields, respectively. We found that both groups adapted their movements to the novel contexts, however, ET patients adapted to a lesser extent compared to healthy volunteers. Importantly, we decomposed movements into components linked to anticipation, preserved here, and real-time execution, which were responsible for the adaptation deficit. Altogether, our results suggest that execution deficits may be a specific functional consequence of the alteration of neural pathways associated with ET. Significance StatementWe tested Essential Tremor patients adaptation abilities in classical tasks including saccadic adaptation to target jumps and reaching adaptation to force field disturbances. Patients adaptation was present but impaired in both tasks. Interestingly, the deficits were mainly present during movement execution, while the anticipatory components of movements were similar to healthy volunteers. These findings reinforce the hypothesis of a cerebellar origin for essential tremor and details the motor adaptation impairments previously found in this disorder.

neuroscience↗

bioRxiv2022

Alterations of oral microbiota and impact on the gut microbiome in type 1 diabetes mellitus revealed by multi-omic analysis

BackgroundAlterations of the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain-resolved, integrated multi-omic analyses of saliva and stool samples collected from eight families with multiple cases of type 1 diabetes mellitus (T1DM). ResultsWe identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain-variants from the oral cavity to the gut at the metagenomic, metatranscriptomic and metaproteomic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract. ConclusionsAlterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of "oral-to-gut" transfer of Streptococcus salivarius. Our results indicate that the observed oral-cavity-driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi-omic analyses, we resolve strain-variant "mouth-to-gut" transfer in a disease context.

microbiology↗