Demyelination

Multiple sclerosis (MS) is by far one of the most commonly occurring demyelinating neuroinflammatory diseases of young adults that is characterized by degradation of the myelin sheath of axons resulting eventually in permanent neurological deficits. Several mediators of the kallikrein-kinin system (KKS) have been identified to be critical contributors to MS pathogenesis and potent direct modulators of neurological functions. In this context, high levels of plasma prekallikrein (PK) were found in active central nervous system (CNS) lesions of MS patients. Recently, Kv7 channels that generate th

Accumulation of heavy metals (Mn and Ni) and prolonged exposure to stress are associated with adverse health outcomes. Various studies have elucidated individually the impacts of stress and metal exposures on brain constituents and function. However, no study has examined the effects of co-exposure to stress, Mn, and Ni in the brain. This study addresses this gap by evaluating oxidative and glial responses, apoptotic activity, as well as cognitive processes in a rat model. Adult Wistar rats were exposed to vehicle (control), restraint stress, 25mg/kg of manganese (Mn) or nickel (Ni), and combi

…manifest as losses in connections or demyelination of axons. When the SC of the brain is damaged, the functional connectivity (FC, i.e. the dynamic interactions and information exchange between distinct brain regions) is locally and globally perturbed. Despite the close correlation between SC and FC, they are not identical; FC exhibits greater flexibility and can reorganize in resp

In multiple sclerosis (MS), oligodendrocyte (OL) degeneration and subsequent demyelination in the central nervous system (CNS) causes neurological impairment. Monocarboxylate transporter 8 (MCT8) may promote OL maturation and myelination by actively transporting thyroid hormone (TH) into the CNS and thereby facilitating key transcription and metabolomic pathways for myelin biogenesis. Diiodothyropropionic acid (DITPA), a synthetic TH-analog, can be transported into the CNS, independent of MCT8 and may promote OL maturation and myelination. In this study, we investigated the potential of DITPA

Calcium is a key intracellular messenger that regulates many vital cellular processes. Calcium signals in oligodendrocytes, the myelinating glia of the CNS, are known to translate environmental information to cellular processes such as proliferation, differentiation and myelination. Myelination is an adaptive process that depends on neuronal activity. We recently demonstrated that neuronal activity in vivo enhances remyelination in demyelinated lesions (Ortiz et al., 2019, JCI Insight). Here, we investigate whether calcium singal in oligodendroglia play a role in remyelination and whether beha

Peripheral diabetic neuropathy (DN) affects 50% of Diabetes Mellitus (DM) patients and approximately 40-50% progress to painful diabetic neuropathy (pDN). Risk factors for pDN include high alcohol consumption, obesity, and low vitamin D levels, all associated with impaired oligodendrocyte progenitor cell (OPC) differentiation. Additionally, studies indicate that depletion of mature myelinating oligodendrocytes induces nociceptive responses in mice. These findings suggest that DM might disrupt oligodendrocyte dynamics, causing defects in central nervous system (CNS) myelin and the onset of neur

Peripheral nerve degeneration (PND) regulated by Schwann cells in a hydrogen sulfide (H2S)-pathway-dependent manner is well known, but the underlying molecular properties of Schwann cells during PND are unclear. We investigated H2S signaling in in vitro- and ex vivo-dedifferentiated Schwann cells as unipotent stem cells by using global proteomics (LC-MS) and transcriptomics (whole-genome and small RNA-sequencing [RNA-seq]) methods. The multi-omics analyses identified several genes and proteins related to oxidative stress, such as Sod1, Gnao1, Stx4, Hmox2, Srxn1, and Edn1. The responses to oxid

Intracerebral haemorrhage (ICH) is the second-most common form of stroke. Due to the post-ICH brain damage and limited therapeutic strategies, the disability rate among ICH survivors is high. DJ-1 is a protein known to play roles in cytoprotection. However, DJ-1 can be oxidised and lose its protective functions. Our study investigated the oxidation state of DJ-1 after ICH and the therapeutic potential of DJ-1 oxidation inhibitor, DJ-1-binding compound 23 (Comp-23), in ICH. We induced experimental ICH mice models by intra-striatal injection of collagenase. Immunoblot, qPCR measurement and immun

…system pathology in response to demyelination of the CNS white matter and sciatic nerve crush. We showed that IL-33 is produced exclusively by non-myelinating oligodendrocytes in the intact white

Hereditary Spastic Paraplegia 4 (HSP-SPG4) is a rare neurodegenerative disease characterized by degeneration of the corticospinal tract caused by mutations of the SPAST gene encoding Spastin, a microtubule-severing protein. We recently showed that gain-of-function cytotoxicity of the M1 isoform of Spastin is sufficient to account for the disease. As a result of the toxic properties of mutant-M1, microtubules in the corticospinal tracts become less acetylated, while the activity of Histone Deacetylates 6 (HDAC6) is correspondingly increased. In addition, it has been reported that Tau, a regulat

Type 2 spastic paraplegia (SPG2) is a rare genetic disorder caused by null mutations in the gene encoding for the proteolipid protein 1, essential for myelin sheath formation around nerve fibers in the central nervous system (CNS). SPG2 manifests as progressive stiffness and weakness in the legs, accompanied by white matter abnormalities and axonal degeneration in the CNS. These myelin abnormalities impair neural communication, impacting motor function, cognition and may contribute to neuropsychological conditions like anxiety. Leriglitazone, a brain-penetrant PPARγ full agonist, has shown

…involving inflammation, cell death, demyelination, and scar formation. How the individual types and subtypes of cells of the central nervous system coordinate to mediate this response remains unclear. While much of our current knowledge is derived from rodents, therapies effective in these models have not translated successfully to clinical trials. Understanding molecular responses across species—lower vertebrates, non-primate mammals, and primates—is crucial for formulating effective human treatments. We aim to u

…Despite the critical role of demyelination in MS, existing treatments do not halt disease progression or promote myelin regeneration. Recent insights from our lab underscore microRNA-145 (miR-145) as a pivotal factor hindering oligodendrocyte production, with elevated levels detected in chronic lesions of secondary progressive MS post-mortem brain tissue. To unveil t

…of oligodendrocytes and/or myelin (demyelination) occurs in traumatic brain injury or pathologies such as multiple sclerosis. Since, there is no specific treatment for demyelination; we are interested in enhancing myelin endogenous repair. We focus our work on A Disintegrin and Metalloprotease (ADAM) 10, the major CNS α-secretase, which generates the neuroprotective soluble fragment sAPPα via cleavage of the Amyloid Precursor Protein

Lead (Pb), a ubiquitous, non-biodegradable heavy metal contaminant, has significant impact on human and animal health. The adverse effect of lead on avian health and productivity has received little attention, considering the fact that they are sentinels. Alchornea laxiflora (Benth), family Euphorbiaceae, grows naturally in the Nigerian rain forest. Decoction of the leaves is administered traditionally to treat inflammatory and infectious diseases. Ethanol extract of Alchornea laxiflora (EaAL) leaves was used in this study to ameliorate lead-induced neurodegeneration. Five-week-old cockerels,

Adenosine A1 receptor (A1AR) signaling exerts important functions in the central nervous system (CNS). Among all CNS cell types, oligodendrocyte (OL) lineage cells possess the highest A1AR expression levels. However, in vivo data regarding the functions of A1ARs in OL lineage cells remain elusive. Here, we first generated NG2-CreERT2xA1ARfl/fl conditional knockout (cKO) mice to specifically delete A1ARs from oligodendrocyte precursor cells (OPCs) upon tamoxifen administration. Immunohistochemical analysis for OL lineage markers PDGFRα, APC CC1, as well as BrdU incorporation detected unaltered

Ether phospholipid synthesis has been genetically and physiologically linked to neurodevelopmental diseases like ADHD and autism. However, so far it is unclear whether plasmalogen or non-plasmalogen ether lipid species mediate this association. To address this, we compared two distinct mouse models, namely Gnpat KO and Peds1 KO, and wild-type controls. Glyceronephosphate O-acyltransferase (GNPAT) initiates the formation of the defining ether bond inside peroxisomes; lack of this enzyme abolishes the biosynthesis of all ether lipids. Plasmanylethanolamine desaturase (PEDS1, TMEM189) completes p

…in the CNS, their role in preventing demyelination, neuronal degeneration and neuroinflammation is unclear. Th

The connection between the right and left hippocampi is implicated in recognition memory. Demyelination in the hippocampal formation and fornix is an early event in Alzheimer's disease (AD). Preliminary studies from our group have shown demyelination in the hippocampal commissure both in animal models and in magnetic resonance imaging of AD patients, which could lead to abnormal oscillatory coupling between both hippocampi and diminished interhemispheric connectivity between the temporal lobes. Our objective was to analyze whether AD patients show alterations in oscillatory coupling between th

Myelin producing human oligodendrocytes express the main thyroid hormone plasma membrane transporter, monocarboxylate transporter 8 (MCT8). Our group has demonstrated that MCT8 is dysfunctional in conditions of developmental or acquired myelin diseases such as progressive multiple (MS). Small molecules that can bypass MCT8, such as the thyroid hormone analog, diiodothyropropionic acid (DITPA), may improve re-myelination and provide neuroprotection in the central nervous system (CNS), following immune-mediated damage described in a mouse model that mimics MS-like disease.Using the myelin oligod

…disease that courses with both demyelination and inflammation. We used two different animal models to recapitulate different aspects of this disease, experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ) induced demyelination. To study the differential response of the CNS, we compared the proteomic profile of EAE mice (at peak disease) and CPZ mice (in the acute phase) in two different CNS regions: somatosensorial cortex (Cx) and spinal cord (SC). Our resul

…of the disease, such as inflammation, demyelination, axonal damage and remyelination, however the exact mechanisms controlling their transformation towards a protective or devastating phenotype during the disease progression remains largely unknown until now. We wish to

…However, a deeper understanding of how demyelination alters the timing, synchrony

…matter microglia show early signs of demyelination.5 T cells are also frequently present in advanced stages of MS and have a tissue resident memory (Trm) phenotype, are more frequently CD8+ then CD4+, are located perivascular, enriched in act