Biology subjects

Sarrazin, N.

Publications and source records attributed to Sarrazin, N..

3 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↗

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↗

bioRxiv2020

Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements

In human, execution of unimanual movements requires lateralized activation of the primary motor cortex, which then transmits the motor command to the contralateral hand through the crossed corticospinal tract (CST). Mutations in NETRIN-1 alter motor control lateralization, leading to congenital mirror movements. To address the role of midline Netrin-1 on CST development and subsequent motor control, we analyzed the morphological and functional consequences of floor-plate Netrin-1 depletion in conditional knock-out mice (Shh::cre;Ntn1lox/lox mice). Here, we show that depletion of floor plate Netrin-1 critically disrupts midline crossing of the CST, whereas the other commissural systems are mostly preserved. The CST defect results in abnormal but functional ipsilateral projections, and is associated with abnormal symmetric movements. Therefore, our study reveals a new role for Netrin-1 in CST development. It also describes a unique mouse model recapitulating characteristics of human congenital mirror movements, through abnormal CST decussation.

neuroscience↗