Biology subjects

Morisset-Lopez, S.

Publications and source records attributed to Morisset-Lopez, S..

3 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↗

bioRxiv2025

TARGETING 5-HT7 RECEPTOR WITH BIASED LIGANDS TO ALLEVIATE PAIN AND SPINAL NEUROINFLAMMATION

The serotonin 5-HT7 receptor (5-HT7R), a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs) is highly expressed in the central nervous system (CNS) and represents a promising target for treating CNS disorders such as sleep disturbances, migraine, neuropsychiatric conditions, and neuropathic pain. Owing to its therapeutic potential, extensive efforts have focused on developing selective 5-HT7R ligands. In the last decades, biased signalling has emerged as a key concept in GPCR pharmacology as biased ligands can stabilize specific active states of the receptor and trigger selective activation of downstream signaling pathways. In this context, we recently identified two biased 5-HT7R ligands, Serodolin and MOA51, from different chemical series. Here, we aimed to compare the pharmacological and safety profiles of these ligands and to assess their effect on pain-related behaviors and spinal neuroinflammation. In inflammatory pain models (acid acetic writhing, formalin and CFA tests), both serodolin and MOA51 effectively attenuated pain responses to a similar extend. Furthermore, in neuropathic pain models, spinal nerve injury (SNI) and Cuff model, both ligands reversed mechanical allodynia. Interestingly, unlike pregabalin, a clinically used reference drug, neither Serodolin nor MOA51 induced apparent tolerance after 10 consecutive days of administration. Treatment with these 5-HT7R ligands also reduced spinal microglial and attenuated neuronal hyperactivity in the spinal cord. Altogether these findings highlight the potential of 5-HT7R-biased ligands as promising analgesic candidates capable of modulating neuroinflammatory processes and mitigating both inflammatory and neuropathic pain.

neuroscience↗

bioRxiv2024

Missense mutation in the activation segment of the kinase CK2 models Okur Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse

Exome sequencing has enabled the identification of causative genes of monogenic forms of autism, amongst them, in 2016, CSNK2A1, the gene encoding the catalytic subunit of the kinase CK2, linking this kinase to Okur-Chung Neurodevelopmental Syndrome (OCNDS), a newly described neurodevelopmental condition with many symptoms resembling those of autism spectrum disorder. Thus far, no preclinical model of this condition exists. Here we describe a knockin mouse model that harbors the K198R mutation in the activation segment of the kinase. This region is a mutational hotspot, representing one-third of patients. These mice exhibit behavioral phenotypes that mirror patient symptoms. Homozygous knock-in (KI) mice die mid-gestation while heterozygous KI mice are born at half of the expected mendelian ratio and are smaller in weight and size than wildtype littermates. Heterozygous KI mice showed alterations in cognition and memory-assessing paradigms, enhanced stereotypies, altered circadian activity patterns, and nesting behavior. Phosphoproteome analysis from brain tissue revealed alterations in the phosphorylation status of major pre- and postsynaptic proteins of heterozygous KI mice. In congruence, we detect reduced synaptic maturation in hippocampal neurons and attenuated long-term potentiation in the hippocampus of KI mice. Taken together, K198R KI mice exhibit significant face validity, presenting ASD-relevant phenotypes, synaptic deficits and alterations in synaptic plasticity, all of which strongly validate this line as a mouse model of OCNDS.

neuroscience↗