Motor neurons and their axons reaching the skeletal muscle have long been considered as the best characterized targets of the degenerative process observed in amyotrophic lateral sclerosis (ALS). However, the involvement of glial cells was also more recently reported. Although oligodendrocytes have been underestimated for a longer time than other cells, they are presently considered as critically involved in axonal injury and also conversely constitute a target for the toxic effects of the degenerative neurons. In the present review, we highlight the recent advances regarding oligodendroglial cell involvement in the pathogenesis of ALS. First, we present the oligodendroglial cells, the process of myelination, and the tight relationship between axons and myelin. The histological abnormalities observed in ALS and animal models of the disease are described, including myelin defects and oligodendroglial accumulation of pathological protein aggregates. Then, we present data that establish the existence of dysfunctional and degenerating oligodendroglial cells, the chain of events resulting in oligodendrocyte degeneration, and the most recent molecular mechanisms supporting oligodendrocyte death and dysfunction. Finally, we review the arguments in support of the primary versus secondary involvement of oligodendrocytes in the disease and discuss the therapeutic perspectives related to oligodendrocyte implication in ALS pathogenesis.

Both Hedgehog and androgen signaling pathways are known to promote myelin regeneration in the central nervous system. Remarkably, the combined administration of agonists of each pathway revealed their functional cooperation towards higher regeneration in demyelination models in males. Since multiple sclerosis, the most common demyelinating disease, predominates in women, and androgen effects were reported to diverge according to sex, it seemed essential to assess the existence of such cooperation in females. Here, we developed an intranasal formulation containing the Hedgehog signaling agonist SAG, either alone or in combination with testosterone. We show that SAG promotes myelin regeneration and presumably a pro-regenerative phenotype of microglia, thus mimicking the effects previously observed in males. However, unlike in males, the combined molecules failed to cooperate in the demyelinated females, as shown by the level of functional improvement observed. Consistent with this observation, SAG administered in the absence of testosterone amplified peripheral inflammation by presumably activating NK cells and thus counteracting a testosterone-induced reduction in Th17 cells when the molecules were combined. Altogether, the data uncover a sex-dependent effect of the Hedgehog signaling agonist SAG on the peripheral innate immune system that conditions its ability to cooperate or not with androgens in the context of demyelination.

Failure of myelin regeneration by oligodendrocytes contributes to progressive decline in many neurological diseases. Here, using in vitro and in vivo rodent models, functional blockade, and mouse brain demyelination, we demonstrate that Sonic hedgehog (Shh) expression in a subset of oligodendrocyte progenitor cells precedes the expression of myelin basic protein (MBP), a major myelin sheath protein. Primary cultures of rodent cortical oligodendrocytes show that Shh mRNA and protein are upregulated during oligodendrocyte maturation before the upregulation of MBP expression. Importantly, almost all MBP-positive cells are Shh positive during differentiation. During remyelination, we identify a rapid induction of Shh mRNA and peptide in oligodendroglial cells present in the demyelinated corpus callosum of mice, including a population of PDGFRα-expressing cells. Shh invalidation by an adeno-associated virus strategy demonstrates that the downregulation of Shh impairs the differentiation of oligodendrocytes in vitro and decreases MBP and myelin proteolipid protein expression in the demyelinated mouse brain at late stages of remyelination. We also report a parallel expression of Shh and MBP in oligodendroglial cells during early post-natal myelination of the mouse brain. Thus, we identify a crucial Shh signal involved in oligodendroglial cell differentiation and remyelination, with potential interest in the design of better-targeted remyelinating therapeutic strategies.

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.

La sclérose en plaques (SEP) est la plus commune des maladies démyélinisantes du système nerveux central (SNC). Elle se caractérise par une succession d'épisodes inflammatoires en partie liés à une dérégulation du système immunitaire et ciblant les cellules synthétisant la myéline, les oligodendrocytes. Ces épisodes sont d'abord suivis de phases de rémission correspondant à la régénération spontanée de la myéline détruite, encore appelée remyélinisation. Cependant, au fur et à mesure de la progression de la pathologie, la remyélinisation échoue notamment en raison d'une modification de l'environnement lésionnel qui devient inadapté au processus de réparation. Cette pathologie chronique et neurodégénérative est à l'heure actuelle considérée comme la première cause de handicaps lourds d'origine non traumatique chez l'adulte jeune. Elle concerne 3 femmes pour 1 homme. Au cours des dernières décennies, de nombreuses molécules visant le système immunitaire ont été identifiées afin de réduire la fréquence des attaques et leur sévérité. Ces molécules sont donc efficaces dans les formes récurrentes-rémittentes, mais deviennent inefficaces quand la maladie progresse. Le défi thérapeutique actuel est par conséquent l'identification de molécules qui permettraient également de favoriser la régénération de la myéline. Le rôle des hormones sexuelles mâles ou androgènes dans les modèles animaux de démyélinisation du SNC a fait l'objet de nombreuses études montrant leurs propriétés immunomodulatrices, neuroprotectrices et remyélinisantes chez le mâle. Puisque les souris femelles et les femmes produisent aussi des androgènes - bien qu'à un niveau beaucoup plus faible que les animaux mâles ou les hommes - l'objectif de mon projet de thèse était de déterminer la contribution des androgènes aux processus de protection et de régénération impliqués dans un contexte de démyélinisation chez les animaux femelles. Dans des modèles immuns (EAE) et non-immuns (LPC) de démyélinisation du SNC, les effets des androgènes ont été analysés par des immunomarquages et la visualisation de l'ultrastructure des axones et de la myéline, par des approches de tri des cellules immunitaires périphériques présentes dans les organes lymphoïdes et infiltrées dans le SNC. Les données indiquent des activités remyélinisantes, anti-inflammatoires et neuroprotectrices majeures des androgènes chez la femelle comme précédemment observé chez le mâle avec néanmoins plusieurs spécificités. Par ailleurs, une analyse transcriptomique de la moelle épinière des animaux EAE nous a conduit à identifier des gènes dont l'expression est dérégulée de façon cohérente avec les données histologiques et fonctionnelles. Ce projet suggère que le maintien d'un taux physiologique d'androgènes doit être pris en considération chez les patientes atteintes de SEP.