Biology subjects

Bachelin, C.

Publications and source records attributed to Bachelin, C..

5 recordsLinked to original sources

bioRxiv2025

Patient-derived lymphocytes drive smoldering lesion pathology in a chimeric multiple sclerosis mouse model

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination, axonal injury, and neurodegeneration. Smoldering lesions-- defined by an inactive core, poor remyelination, and a rim of chronically activated microglia-- are hallmarks of a progressive disease course and correlate with irreversible disability. The mechanisms driving their formation remain poorly understood. Using a chimeric mouse model, we investigated the long-term impact of healthy donors (HD) and MS patient-derived lymphocytes (LY) graft on the evolution of spinal cord demyelinated lesion. Three months post-grafting, only MS-derived LY persisted as perivascular cuffs interacting with vascular and murine immune cells, mirroring MS smoldering lesion pathology. MS LY-grafted mice exhibited impaired functional recovery and slower somatosensory evoked potential (SSEP) conduction compared to controls. Electron microscopy confirmed glial scar formation, persistent demyelination and a lesion architecture with an inflammatory inactive center but active rim. Single-nucleus RNA sequencing revealed an imbalance in CNS cell populations, with MS LY-grafted mice showing reduced neuronal abundance, enriched activated microglia, and immature oligodendroglial profiles, correlating with slower SSEP conduction speeds. Immune cell subclustering identified an enrichment of disease-associated microglia and interferon-responsive microglia in MS LY-grafted mice, marked by elevated pro-inflammatory markers and active myelin phagocytosis. Oligodendroglial cells displayed downregulated myelination and stress-response genes, with disrupted myelin ultrastructure confirmed by electron microscopy. Multiblock analysis revealed donor-specific variability, with some MS LY inducing outcomes akin to HD, while others drove severe pathology. Our model enables mechanistic dissection of the transition from focal to diffuse CNS pathology in MS and captures patient-specific pathophysiological signatures, providing a platform for personalized mechanistic studies and targeted therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/676229v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1168b07org.highwire.dtl.DTLVardef@1018361org.highwire.dtl.DTLVardef@58945eorg.highwire.dtl.DTLVardef@174b7e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

In the central nervous system (CNS), myelin formation by oligodendrocytes (OLs) relies on actin dynamics. Actin polymerization supports the ensheathment step, when the OL process contacts the axon, while a drastic shift to actin depolymerization is required to enable the following step of wrapping and expansion of myelin membranes. The molecular mechanisms triggering this switch, essential for proper myelination, have yet to be elucidated. Here, we identify P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. We show that PAK1 accumulates in OLs in a kinase inhibited form, triggering actin disassembly and, consequently, myelin expansion. Remarkably, we identify NF2/Merlin as an endogenous inhibitor of PAK1 by proteomics analysis of its binding partners. We found that Nf2 knockdown in OLs results in PAK1 activation and impairs myelin formation, and that pharmacological inhibition of PAK1 in Nf2-knockdown OLs rescues these defects. Moreover, we demonstrate that modulating PAK1 activity in OLs controls myelin expansion and provide compelling evidence indicating that specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that PAK1-NF2/Merlin duo plays a key role in actin cytoskeleton remodeling in OLs, required for proper myelin formation. These findings have broad mechanistic and therapeutic implications for demyelinating diseases and neurodevelopmental disorders. SignificanceRemodeling actin cytoskeleton plays a crucial role in myelin formation by oligodendrocytes (OLs). Recent studies have shown that expansion and wrapping of myelin membranes around axons depends on actin depolymerization. However, the molecular mechanisms triggering this key step in myelination are not fully elucidated. Using genetic and pharmacological tools as well as proteomics analyses, we found that PAK1 (P21 Activated Kinase 1) kinase activity is maintained inhibited by NF2/Merlin in OLs to allow actin depolymerization and, consequently, myelin membrane expansion. Pak1 loss-of-function in OLs leads to an increase in myelin thickness in the white matter of adult mice, confirming the role of PAK1 inactivation in myelin membrane expansion.

neuroscience↗

bioRxiv2022

Failed remyelination of the non-human primate optic nerve leads to axon degeneration, retinal damages and visual dysfunction.

White matter disorders of the CNS such as MS, lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue, to prevent neuronal degeneration and promote recovery. Most of these strategies are developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined non-human primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculo-motor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This non-human primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair pro-myelinating/neuroprotective therapies to the clinic for myelin disorders such as MS. Significance StatementPromotion of remyelination has become a new therapeutic avenue, to prevent neuronal degeneration and promote recovery in white matter diseases such as MS. To date most of these strategies are developed in short-lived rodent models of demyelination, which spontaneously repair. Well-defined non-human primate models closer to man would allow to efficiently advance therapeutic approaches. Here we present a non-human primate model of optic nerve demyelination that recapitulates several features of MS lesions. The model leads to failed remyelination, associated with progressive axonal degeneration and visual dysfunction, thus providing the missing link to translate emerging pre-clinical therapies to the clinic for myelin disorders such as MS.

neuroscience↗

bioRxiv2021

Dysregulated functional and metabolic response in multiple sclerosis patient macrophages correlate with a more inflammatory state, reminiscent of trained immunity

In multiple sclerosis (MS), immune cells invade the central nervous system and destroy myelin. Macrophages contribute to demyelination and myelin repair, and their role in each process depends on their ability to acquire specific phenotypes in response to external signals. Here, we assess whether defects in MS patient macrophage responses may lead to increased inflammation or lack of neuro-regenerative effects. To test this hypothesis, CD14+CD16- monocytes from MS patients and healthy controls were activated in vitro to obtain homeostatic-like, pro-inflammatory and pro-regenerative macrophages. Myelin phagocytic capacity and surface molecule expression of CD14, CD16 and HLA-DR were evaluated with flow cytometry. In parallel, macrophages were assessed through RNA sequencing and metabolomics. We observed that MS patient monocytes ex vivo recapitulate their preferential activation toward a CD16+ phenotype, a subset of pro-inflammatory cells present in MS lesions. Even in the absence of pro-inflammatory stimuli, MS patient macrophages exhibit a pro-inflammatory transcriptomic profile with higher levels of cytokine/chemokine suggesting increased recruitment capacities. Interestingly, MS patient macrophages exhibit a specific metabolic signature with a mitochondrial energy metabolism blockage resulting in a shift from oxidative phosphorylation to glycolysis. Furthermore, we observe a failure to up-regulate apoptosis effector genes in the pro inflammatory state suggesting a longer-lived pro-inflammatory macrophage population. Our results highlight an intrinsic defect of MS patient macrophages that provide evidence of innate immune cell memory in MS.

neuroscience↗

bioRxiv2018

Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling

Schwann cells (SC) enter the central nervous system (CNS) in pathophysiological conditions. However, how SC invade the CNS to remyelinate central axons remains undetermined. We studied SC migratory behavior ex vivo and in vivo after exogenous transplantation in the demyelinated spinal cord. Data highlight for the first time that SC migrate preferentially along blood vessel in perivascular ECM, avoiding CNS myelin. We demonstrate in vitro and in vivo that this migration route occurs by virtue of a dual mode of action of Eph/ephrin receptor. Indeed, EphrinB3, enriched in myelin, interacts with SC Eph receptors, to drive SC away from CNS myelin, and triggers their preferential adhesion to ECM components, such as fibronectin via integrin{beta}1 interactions. This complex interplay enhances SC migration along the blood vessel network and together with lesion-induced vascular remodeling facilitates their timely invasion of the lesion site. These novel findings elucidate the mechanism by which SC invade and contribute to spinal cord repair.

neuroscience↗