Biology subjects

Lubetzki, C.

Publications and source records attributed to Lubetzki, C..

9 recordsLinked to original sources

bioRxiv2026

High neuron-microglia interaction at the node of Ranvier predicts recovery in an inflammatory model of Multiple Sclerosis

Microglia, the resident immune cells of the central nervous system, dynamically respond to their environment in health, injury and disease. They contact axons at the nodes of Ranvier in an activity-dependent manner, a process which contributes to repair, but how adaptive immunity in Multiple Sclerosis (MS) impacts this neuron-microglia crosstalk remains unknown. Using an inflammatory MS model, we identify strengthened microglia-node interactions at remission onset, with marked interindividual variability. Increased engagement correlates with a Th2-related cytokine signature, and IL13/IL4 are sufficient to enhance microglia-node contacts. High interaction levels associate with more pro-regenerative microglia, improved tissue repair and better functional recovery. Low-intensity physical exercise at remission onset further promotes microglia-node interaction, pro-regenerative microglia and improves recovery. Consistently, high microglia-node contact in MS tissue is associated with more extensive remyelination, underscoring this interaction as a key process in repair.

neuroscience↗

bioRxiv2025

Neuronal activity promotes repair by microglial reprogramming following demyelination

Microglia, the resident immune cells of the central nervous system (CNS), play a multifaceted role in neurological disorders. In multiple sclerosis (MS), a chronic demyelinating and neurodegenerative disease, microglia contribute to inflammation and tissue damage, but can also support repair by clearing myelin debris, limiting inflammation and promoting remyelination and neuroprotection. The timely transition from their pro-inflammatory to pro-regenerative states is essential for effective repair and, in chronic MS, persistent, defective microglial activation contributes to disease progression. Yet, the mechanisms underlying the microglial switch remain largely unknown. In this study, we demonstrate that neuronal activity can modulate microglial signature at the onset of remyelination in MS models, in a pattern-dependent manner. Transcriptomic analyses reveal a downregulation of pro-inflammatory, disease-associated microglial signatures alongside an upregulation of genes associated with oxidative phosphorylation and lipid metabolism, indicative of a shift toward pro-regenerative states following physiological activity enhancement. This activity-dependent reprogramming also extends to infiltrating monocytes and macrophages, collectively fostering a microenvironment favoring repair.

neuroscience↗

bioRxiv2024

Neuronal activity promotes axonal node-like clustering prior to myelination and remyelination in the central nervous system.

Nodes of Ranvier ensure the fast saltatory conduction along myelinated axons, through their enrichment in voltage-gated sodium and potassium channels. We and others have shown that node-like cluster assembly can occur before myelination. In multiple sclerosis, demyelination is associated with node of Ranvier disassembly, but node-like reassembly can occur prior to remyelination. Given the crucial role of neuronal activity in inducing (re)myelination, we asked whether neuronal activity could regulate node-like clustering. We show that node-like clustering is promoted by neuronal activity and decreased when excitatory glutamatergic receptors are inhibited. Altering glutamatergic neurotransmission leads to the downregulation of Nav1.1 expression, which we show to be critical for node-like clustering. Neuronal activity also promotes node-like clustering in remyelination. As node-like clusters modulate conduction velocity and myelination initiation along axons, we propose that activity-dependent node-like clustering could modulate neuronal network establishment, as well as myelination regulation and patterning during development, plasticity and repair.

neuroscience↗

bioRxiv2023

Deleterious functional consequences of perfluoroalkyl substances accumulation into the myelin sheath

Exposure to persistent organic pollutants during the perinatal period is of particular concern because of the potential increased risk of neurological disorders in adulthood. Here we questioned whether exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) could alter myelin formation and regeneration. First, we show that PFOS, and to a lesser extent PFOA, accumulated into the myelin sheath of postnatal day 21 (p21) mice, whose mothers were exposed to either PFOA or PFOS (20mg/L) via drinking water during late gestation and lactation, suggesting that accumulation of PFOS into the myelin could interfere with myelin formation and function. In fact, PFOS, but not PFOA, disrupted the generation of oligodendrocytes, the myelin-forming cells of the central nervous system, derived from neural stem cells localised in the subventricular zone of p21 exposed animals. Then, cerebellar slices were transiently demyelinated using lysophosphatidylcholine and remyelination was quantified in the presence of either PFOA or PFOS. Only PFOS impaired remyelination, a deleterious effect rescued by adding thyroid hormone (TH). Similarly to our observation in the mouse, we also showed that PFOS altered remyelination in Xenopus laevis using the Tg(Mbp:GFP-ntr) model of conditional demyelination and measuring, then, the number of oligodendrocytes. The functional consequences of PFOS-impaired remyelination were shown by its effects using a battery of behavioural tests. In sum, our data demonstrate that perinatal PFOS exposure disrupts oligodendrogenesis and myelin function through modulation of TH action. PFOS exposure may exacerbate genetic and environmental susceptibilities underlying myelin disorders, the most frequent being multiple sclerosis. HighlightsO_LIOur investigation points the deleterious effects of PFOS incorporation into the myelin sheath C_LIO_LIPFOS interfere dramatically with the generation of remyelinating and functional repair of demyelinating lesions C_LIO_LIOur study points to a potential link between these persistent pollutants and the recent increase in prevalence of multiple sclerosis C_LI

pharmacology and toxicology↗

bioRxiv2022

Alterations of the axon initial segment in multiple sclerosis

Grey matter damage has been established as a key contributor to disability progression in multiple sclerosis. Aside from neuronal loss and axonal transections, which predominate in cortical demyelinated lesions, synaptic alterations have been detected in both demyelinated plaques and normal-appearing grey matter, resulting in functional neuronal damage. The axon initial segment is a key element of neuronal function, responsible for action potential initiation and maintenance of neuronal polarity. Despite several reports of profound axon initial segment alterations in different pathological models, among which experimental auto-immune encephalomyelitis, whether the axon initial segment is affected in multiple sclerosis is still unknown. Using immunohistochemistry, we analyzed axon initial segments from control and multiple sclerosis tissue, focusing on layer 5/6 pyramidal neurons in the neocortex and Purkinje cells in the cerebellum and performed analysis on the parameters known to control neuronal excitability, i.e., axon initial segment length and position. We found that the axon initial segment length was unchanged among the different multiple sclerosis samples, and not different from controls. In contrast, in both cell types, the axon initial segment position was altered, with an increased soma-axon initial segment gap, in both active and inactive demyelinated lesions. In addition, using a computational model, we show that this increased gap between soma and axon initial segment might increase neuronal excitability. Taken together, these results show for the first time changes of axon initial segments in multiple sclerosis, in active as well as inactive grey matter lesions in both neocortex and cerebellum, which might alter neuronal function.

neuroscience↗

bioRxiv2020

Oligodendrocyte secreted factors shape hippocampal GABAergic neuron transcriptome and physiology

Oligodendrocytes form myelin for central nervous system axons and release factors which signal to neurons during myelination. Here, we ask how oligodendroglial factors influence hippocampal GABAergic neuron physiology. In mixed hippocampal cultures GABAergic neurons fired action potentials of short duration and received high frequencies of excitatory synaptic events. In purified neuronal cultures without glial cells, GABAergic neuron excitability increased and the frequency of synaptic events decreased. These effects were largely reversed by adding oligodendrocyte conditioned medium. We compared the transcriptomic signature with the electrophysiological phenotype of single neurons in these three culture conditions. Genes expressed by single pyramidal or GABAergic neurons largely conformed to expected cell-type specific patterns. Multiple genes of GABAergic neurons were significantly downregulated by the transition from mixed cultures containing glial cells to purified neuronal cultures. Levels of these genes were restored by the addition of oligodendrocyte conditioned medium to purified cultures. Clustering genes with similar changes in expression between different culture conditions revealed processes affected by oligodendroglial factors. Enriched genes are linked to roles in synapse assembly, action potential generation and transmembrane ion transport, including of zinc. These results provide new insight into the molecular targets by which oligodendrocytes influence neuron excitability and synaptic function.

neuroscience↗

bioRxiv2020

Genetically-Modified Macrophages Accelerate Myelin Repair

Preventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents degeneration of demyelinated axons, promoting this process in patients might halt the development of permanent disability. In demyelinating mouse lesions, local overexpression of Semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases OPC recruitment and remyelination. However, molecular targeting to MS lesions is a challenge because these are disseminated in the central nervous system. We hypothesized that a clinically-relevant paradigm to deliver Sema3F to demyelinating lesions and increase OPC recruitment may be to use blood-derived macrophages as vehicles. Thus, we chose transplantation of genetically-modified hematopoietic stem cells (HSCs) as means of obtaining circulating monocytes that overexpress Sema3F. We first demonstrated that the supernatant from Sema3F-lentiviral vector transduced HSCs stimulates OPC migration in Neuropilin 2 (Nrp2, Sema3F receptor)-dependent fashion. We then investigated whether OPCs remain responsive to Sema3F with age. While Sema3F expression in the lesions of middle-aged and old mice (characterized by decreased efficiency of OPC recruitment and remyelination) was decreased, middle-aged OPCs retained Nrp2 expression and migrated in response to both recombinant Sema3F and Sema3F-transduced cell supernatant in vitro. We then investigated whether blood cells engineered to overexpress Sema3F can target demyelinating CNS lesions and improve remyelination. Thus, we transplanted Sema3F-transduced HSCs and obtained chimeric mice (with Sema3F overexpression in blood cells), in which we induced demyelinating spinal cord lesions. Transgene-carrying cells, predominantly macrophages, quickly infiltrated lesions in both control and Sema3F chimeras. While infiltration of Sema3F-expressing cells did not alter the inflammatory status of the lesions nor OPC survival, it increased OPC recruitment, which accelerated the onset of remyelination. Our results provide a proof-of-concept that blood cells, particularly monocyte-derived macrophages, can be used to deliver pro-remyelinating agents "at the right time and place", suggesting novel means for remyelination-promoting strategies.

neuroscience↗

bioRxiv2020

Microglia-neuron communication at nodes of Ranvier depends on neuronal activity through potassium release and contributes to myelin repair.

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity. In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. The mechanisms for microglia-neuron communication remain largely unkown. Here, we identify nodes of Ranvier as a direct and stable site of interaction between microglia and axons, in both mouse and human tissue. Using dynamic imaging, we highlight the preferential interaction of microglial processes with nodes of Ranvier along myelinated fibers. We show that microglianode interaction is modulated by neuronal activity and associated potassium release, with THIK-1 ensuring their microglial read-out. Disrupting axonal K+ flux following demyelination polarizes microglia towards a pro-inflammatory phenotype and decreases remyelination rate. Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron communication, participating in the pro-remyelinating effect of microglia after myelin injury.

neuroscience↗

bioRxiv2019

An alternative mechanism of early nodal clustering and myelination onset in GABAergic neurons of the central nervous system

In vertebrates, fast saltatory conduction along myelinated axons relies on the node of Ranvier. How nodes assemble on CNS neurons is not yet fully understood. We recently highlighted that clusters similar to nodes can form prior to myelin deposition in hippocampal GABAergic neurons and are associated with increased conduction velocity. Here, we used a live imaging approach to characterize the intrinsic mechanisms underlying the assembly of these early clusters. We first demonstrated that their components can partially pre-assemble prior to membrane targeting and determined the molecular motors involved in their trafficking. We then demonstrated the key role of the protein {beta}2Nav for clustering initiation. We further unraveled the fate of these early clusters, by showing that they participate in node formation, but also have an unexpected role in guiding oligodendrocyte processes prior to myelin deposition. Altogether our results shed light on an alternative mechanism of nodal clustering and myelination onset.

neuroscience↗