Biology subjects

Degano, A. L.

Publications and source records attributed to Degano, A. L..

4 recordsLinked to original sources

bioRxiv2026

Disruption of Myelin-Associated Glycoprotein Activity Drives Aberrant Cerebellar Neurodevelopment and Autism-Like Behaviors.

Immune-mediated mechanisms have emerged as important contributors to neurodevelopmental vulnerability in a subset of autism spectrum disorder (ASD) cases. Circulating IgG antibodies against myelin-associated glycoprotein (MAG) have been reported in individuals with ASD and their mothers; however, the pathogenic relevance of these antibodies and the contribution of MAG signaling to neurodevelopment remain unclear. Here, we investigated whether disruption of MAG function during early postnatal life is sufficient to alter cerebellar development and induce ASD-relevant behavioral alterations. Using complementary genetic and immunological approaches, we show that constitutive deletion of Mag or transient postnatal blockade with a function-blocking anti-MAG antibody induces region-specific alterations in cerebellar development. MAG disruption results in excessive proliferation of granule cell precursors followed by delayed, region-restricted neuronal death, together with persistent abnormalities in Purkinje neuron number and dendritic maturation. These structural changes occur in the absence of major or persistent demyelination, consistent with dysregulation of myelin-associated developmental signaling rather than myelin loss. Importantly, early postnatal passive immunization with anti-MAG IgG is sufficient to induce significant impairments in social communication, sociability, and social recognition, recapitulating core behavioral domains relevant to ASD. Together, these data provide experimental evidence that immune-mediated interference with a myelin-associated signaling molecule can disrupt cerebellar development during critical postnatal windows and produce long-lasting behavioral consequences. Our findings identify MAG as a previously underappreciated regulator of neurodevelopment and support a model in which antibody-mediated perturbation of myelin-derived instructive signaling contributes to ASD-relevant phenotypes, aligning with emerging frameworks of immune-linked neurodevelopmental vulnerability. HighlightsO_LIDisruption of myelin-associated glycoprotein (MAG) activity during early postnatal life alters cerebellar development in a region-specific manner. C_LIO_LIGenetic deletion or antibody-mediated blockade of MAG function induces granule cell dysregulation and Pkn structural abnormalities without overt demyelination. C_LIO_LIPassive immunization of anti-MAG antibodies is sufficient to induce autism-like behavioral phenotypes, supporting a causal immune-mediated mechanism. C_LIO_LIThese findings identify myelin-associated signaling as a novel contributor to neurodevelopmental dysfunction and align with the maternal autoantibody-related ASD framework. C_LI

neuroscience↗

bioRxiv2021

Glial Cell Responses to constant low Light exposure in Rat Retina.

Retinal damage promoted by constant illumination of low intensity resulted in a diminution in classical photoreceptors cells. Glial cells exert profound effects on neurons, vasculature and other glial cells. Macroglia and microglia with specific morphological, physiological, and antigenic characteristics may play an essential role in both the maintenance and control of retinal homeostasis, or to exert mechanisms that promote cell death. The role of glial cells and immune function in the pathogenesis promoted by low light is poorly understood. We performed glial cells characterization along the time-course of retinal degeneration induced by chronic exposure to low intensity of light in Wistar rats. We exposed the animals at constant light from 2 to 8 days and assessed the retinal glia. After 6 days of light exposure, retinas presented increased levels of GFAP, a macroglia marker and microglia markers Iba1 and CD68 displayed increased mRNA levels after 6 days. The number of Iba1 positive cells increased in the outer nuclear layer, showing ameboid morphology with thicker processes characteristic of microglial activated cells. The expression levels of immune mediators TNF-{square} and IL-6 were also significantly increased after 6 days. Finally, chemokines analysis showed that CX3CR1 and CCL2 expression levels were significantly elevated after 6 days. Hence, all the events of glial activation occurred after 5-6 days of constant light exposure, when the number of cells of the outer nuclear layer has already decreased significantly. Herein we demonstrated that glial and immune activation are secondary to neurodegeneration; in this scenario, our results suggest that photoreceptor death is an early event that may be induced by phototransduction-dependent mechanisms.

neuroscience↗

bioRxiv2020

MECP2 DEFICIENCY ALTERS M1/M2 GENE EXPRESSION IN BONE MARROW-DERIVED MACROPHAGES UPON STIMULATION

Rett Syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in the X-linked gene, MeCP2, which encodes for methyl-CpG binding protein 2 (MeCP2). MeCP2 is member of a family of methyl binding proteins that control the expression of several genes according to the genomic context. Emerging evidence suggests that immune dysfunctions would actively contribute to the pathogenesis of RTT. Macrophages are key effector cells that participate in several critical aspects of immune responses. The aim of our work was to assess the response of macrophages in vitro in the context of polarizing stimuli. We used bone marrow-derived macrophages (BMDM) obtained from MeCP2308/y mice, a mouse model that carries a truncated form of MeCP2. Since MeCP2 is expressed as a "partially functional" protein in humans with RTT it becomes crucial to establish how the presence of a mutant form of MeCP2 affects immune responses to support the normal homeostasis of individuals. MeCP2 deficiency induced exacerbation of pro-inflammatory mediators and deficient immune regulatory responses under polarizing conditions. These findings suggest that MeCP2 plays a role in the establishment of macrophage polarization in the context of immune activation. Present results may have important implications in understanding RTT pathogenesis and for developing potential treatments. Conflict of interestThe authors declare no conflicts of interest.

immunology↗

bioRxiv2020

MeCP2 deficiency exacerbates the neuroinflammatory setting and autoreactive response during an autoimmune challenge: implications for Rett Syndrome.

Background: Rett syndrome is a severe and progressive neurological disorder linked to mutations in the MeCP2 gene located on the X chromosome. So far it has not been established how the presence of a mutant form of MeCP2 can maintain essential regulation of immune responses to support the normal homeostasis of individuals. Since MeCP2 is mostly expressed as a "partially functional" protein in humans with RTT, the aim of our work was to evaluate whether a mutation in MeCP2 interferes with the induction of neuroinflammatory responses in real time. Methods: We used MeCP2308/y mouse model (MUT) and exposed it to an autoimmune challenge, experimental autoimmune encephalomyelitis (EAE). WT and MUT mice were immunized with CFA-MOG or CFA alone (control) and clinical scores were evaluated daily. Animals were sacrificed at either 12 days post-induction (dpi, acute stage) or 30 dpi (chronic stage) and spleen and spinal cord were collected from individual mice for further studies. Cellular infiltration and microgliosis was evaluated by IHC. Cytokine production was assessed in spinal cord and in cultured splenocytes after MOG activation ex-vivo by cytometry and real time RT-PCR. Results: Our results showed that MeCP2 deficiency increased the susceptibility to develop EAE, along with a defective induction of anti-inflammatory responses and an exacerbated MOG-specific reactivity with high IFN{gamma} expression in peripheral immune sites. During the chronic stage, an increase in gene expression of pro-inflammatory cytokines (IFN{gamma}, TNF and IL-1{beta}) and downregulation of genes relevant for immune regulation (IL-10, FoxP3 and CX3CR1) was found in MUT-EAE spinal cords. Conclusions: This is the first study performed in a MeCP2 mutant mouse model that explores the pathophysiology and neuroinflammation in the context of an autoimmune challenge. We could establish that an MeCP2 mutation act intrinsically affecting neuroimmune interactions by promoting an inflammatory environment and a deficient immune regulatory setting. These results are relevant for understanding the consequences of MeCP2 mutations on immune homeostasis in MeCP2-related disorders, as well as setting the bases for further therapeutic interventions that consider the immune status in patients.

neuroscience↗