Biology subjects

Raoul, C.

Publications and source records attributed to Raoul, C..

4 recordsLinked to original sources

bioRxiv2026

Dysregulation of LINGO1 expression in the SOD1(G93A) mutant mice during symptomatic stages of the disease and early postnatal oligodendrogenesis

Oligodendrocytes play an essential role in axonal metabolic support and myelination, and their dysfunction is associated with amyotrophic lateral sclerosis (ALS). LINGO1 is a major inhibitor of oligodendrocyte differentiation and axonal regeneration, identified as a promising therapeutic targeted for inflammatory demyelinating diseases. Here, we investigated the expression pattern of LINGO1 in the well-established SOD1(G93A) transgenic mouse model of ALS. We show that LINGO1 protein expression is significantly elevated in both grey and white matter of the mutant spinal cord during both the symptomatic and end stages of the disease. LINGO1 is also notably co-expressed with astroglial and neuronal markers. However, neither the levels of LINGO1 transcripts, nor levels of microRNAs predicted to regulate its expression were altered in the mutant spinal cord, suggesting the involvement of alternative regulatory mechanisms. Our analysis of microRNAs revealed in the mutant a significant downregulation of miR-138, a microRNA known to promote myelination. The differential expression of LINGO1 and miR-138 in ALS mice thus may drive deleterious processes during disease progression in adulthood. Moreover, our data show that white-matter pathology arises earlier than initially thought, as evidenced by significant alterations of oligodendrogenesis that manifest as early as postnatal day 5. Study of the molecular determinants of this developmental defect shows increased miR-138 expression, which may promote oligodendrocyte progenitor cell maturation and involve compensatory mechanisms. Overall, our work identifies disrupted expression of LINGO1 and/or miR-138 in brain during early oligodendrogenesis and at symptomatic disease stages. These findings open the way to further investigations that may consider miR-138 as a potential presymptomatic biomarker and LINGO1 as a therapeutic target to promote remyelination in the context of ALS.

neuroscience↗

bioRxiv2024

Exercise and disease state influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1G93A amyotrophic lateral sclerosis (ALS) mouse model

BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1G93A ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1G93A ALS mice could lead to differential and potentially improved benefits. MethodsWe thus investigated the contribution of Fn14 to disease phenotypes in the SOD1G93A ALS mice. To do so, Fn14 knockout mice (Fn14-/-) were crossed onto the SOD1G93A background to generate SOD1G93A;Fn14-/- mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14-/-, SOD1G93A and SOD1G93A;Fn14-/-). ResultsHere, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1G93A mice. We then show that Fn14-depleted SOD1G93A mice display an increased lifespan and decreased muscle pathology, without an impact on motor function, and that this is dependent on exposure to exercise. Indeed, we observe that endurance (rotarod) and resistance (grid test) exercises influence the positive effects of Fn14 deletion on survival and muscle phenotypes in SOD1G93A mice, which may be further influenced by genotype and disease state. ConclusionsOur study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease and metabolic state. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism and exercise will be of importance in future studies.

pathology↗

bioRxiv2022

Differential effect of Fas activation on spinal muscular atrophy motoneuron death and induction of axonal growth

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most common motoneuron diseases affecting adults and infants, respectively. ALS and SMA are both characterized by the selective degeneration of motoneurons. Although different in their genetic etiology, growing evidence indicate that they share molecular and cellular pathogenic signatures that constitute potential common therapeutic targets. We previously described a motoneuron-specific death pathway elicited by the Fas death receptor, whereby vulnerable ALS motoneurons show an exacerbated sensitivity to Fas activation. However, the mechanisms that drive the loss of SMA motoneurons remains poorly understood. Here, we describe an in vitro model of SMA-associated degeneration using primary motoneurons derived from Smn2B/- SMA mice and show that Fas activation selectively triggers death of the proximal motoneurons. Fas-induced death of SMA motoneurons has the molecular signature of the motoneuron-selective Fas death pathway that requires activation of p38 kinase, caspase-8, -9 and -3 as well as upregulation of collapsin response mediator protein 4 (CRMP4). In addition, Rho Kinase (ROCK) is required for Fas recruitment. Remarkably, we found that exogenous activation of Fas also promotes axonal elongation in both wildtype and SMA motoneurons. Axon outgrowth of motoneurons promoted by Fas requires the activity of ERK, ROCK and caspases. This work defines a dual role of Fas signaling in motoneurons that can elicit distinct responses from cell death to axonal growth.

neuroscience↗

bioRxiv2021

Expression of a miRNA targeting mutated SOD1 in astrocytes induces motoneuron plasticity and improves neuromuscular function in ALS mice

In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell-autonomous and non-cell-autonomous mechanisms lead to the selective degeneration of motoneurons. Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1G93A protein. An AAV-gfaABC1D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of fast-fatigable motoneurons until disease end stage. In the gastrocnemius muscle of the treated SOD1G93A mice, the fast-twitch type IIb muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/re-innervation events. The transcriptome profiling of spinal cord motoneurons shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes provides therapeutic effects enhancing motoneuron plasticity and improving neuromuscular function in ALS mice.

neuroscience↗