Search Results (48)

Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer’s disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases. Full article

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson’s disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation. Full article

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults. The accumulation of undegraded VLCFA in glial cell membranes and myelin has long been thought to be the central mechanism of X-ALD. Methods: This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis. Results: In the Abcd1 knockout (KO) mouse that mimics the spinal cord disease, the late manifestations of axonopathy are rapidly reversed by ABCD1 gene transfer into spinal cord oligodendrocytes (OLs). In a peroxin-5 KO mouse model, the selective impairment of peroxisomal biogenesis in OLs achieves an almost perfect phenocopy of cerebral ALD. A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells. Other mouse models showed the critical role of OLs in providing energy substrates to axons. In addition, studies on microglial changing substates have improved our understanding of neuroinflammation. Conclusions: Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms. Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons. Full article

DNA methylation and demethylation are key epigenetic events that regulate gene expression and cell fate. DNA demethylation via oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is typically mediated by TET (ten-eleven translocation) enzymes. The 5hmC modification is considered an intermediate state of DNA demethylation; it is particularly prevalent in the brain and is believed to play a role in the development of many cell types in the brain. Our previous studies have identified that vitamin C (Vc) and MEK inhibitor PD0325901 could significantly promote OPC (oligodendrocyte progenitor cell)-to-OL (oligodendrocyte) differentiation. Here we discovered that Vc and PD0325901 may promote OPC-to-OL differentiation by inducing DNA demethylation via hydroxymethylation. Blocking 5hmC formation almost totally blocked Vc- and PD0325901-stimulated OPC-to-OL differentiation. In addition, TET1 is not involved in Vc,- and PD0325901-promoted OL generation. We also found a synergistic effect between the two compounds in inducing OL generation, suggesting the possibility of a combination therapy for demyelination diseases in the future. Full article

If the billions of oligodendrocytes (OLs) populating the central nervous system (CNS) of patients could express their feelings, they would undoubtedly tell gene therapists about their frustration with the other neural cell populations, neurons, microglia, or astrocytes, which have been the favorite targets of gene transfer experiments. This review questions why OLs have been left out of most gene therapy attempts. The first explanation is that the pathogenic role of OLs is still discussed in most CNS diseases. Another reason is that the so-called ubiquitous CAG, CBA, CBh, or CMV promoters—widely used in gene therapy studies—are unable or poorly able to activate the transcription of episomal transgene copies brought by adeno-associated virus (AAV) vectors in OLs. Accordingly, transgene expression in OLs has either not been found or not been evaluated in most gene therapy studies in rodents or non-human primates. The aims of the current review are to give OLs their rightful place among the neural cells that future gene therapy could target and to encourage researchers to test the effect of OL transduction in various CNS diseases. Full article

Background: Perinatal infection is a major risk factor for diffuse white matter injury (dWMI), which remains the most common form of neurological disability among very preterm infants. The disease primarily targets oligodendrocytes (OL) lineage cells in the white matter but also involves injury and/or dysmaturation of neurons of the gray matter. This study aimed to investigate whether neuroinflammation preferentially affects the cellular compositions of the white matter or gray matter. Method: Neuroinflammation was initiated by intracerebral administration of lipopolysaccharide (LPS) to rat pups at postnatal (P) day 5, and neurobiological and behavioral outcomes were assessed between P6 and P21. Results: LPS challenge rapidly activates microglia and astrocytes, which is associated with the inhibition of OL and neuron differentiation leading to myelination deficits. Specifically, neuroinflammation reduces the immature OLs but not progenitors and causes acute axonal injury (β-amyloid precursor protein immunopositivity) and impaired dendritic maturation (reduced MAP2+ neural fiber density) in the cortical area at P7. Neuroinflammation also reduces the expression of doublecortin in the hippocampus, suggesting compromise in neurogenesis. Utilizing a battery of behavioral assessments, we found that LPS-exposed animals exhibited deficits in sensorimotor, neuromuscular, and cognitive domains. Conclusion: Our overall results indicate that neuroinflammation alone in the early postnatal period can produce cardinal neuropathological features of dWMI. Full article

Axons wrapped around the myelin sheath enable fast transmission of neuronal signals in the Central Nervous System (CNS). Unfortunately, myelin can be damaged by injury, viral infection, and inflammatory and neurodegenerative diseases. Remyelination is a spontaneous process that can restore nerve conductivity and thus movement and cognition after a demyelination event. Cumulative evidence indicates that remyelination can be pharmacologically stimulated, either by targeting natural inhibitors of Oligodendrocyte Precursor Cells (OPCs) differentiation or by reactivating quiescent Neural Stem Cells (qNSCs) proliferation and differentiation in myelinating Oligodendrocytes (OLs). Although promising results were obtained in animal models for demyelination diseases, none of the compounds identified have passed all the clinical stages. The significant number of patients who could benefit from remyelination therapies reinforces the urgent need to reassess drug selection approaches and develop strategies that effectively promote remyelination. Integrating Artificial Intelligence (AI)-driven technologies with patient-derived cell-based assays and organoid models is expected to lead to novel strategies and drug screening pipelines to achieve this goal. In this review, we explore the current literature on these technologies and their potential to enhance the identification of more effective drugs for clinical use in CNS remyelination therapies. Full article

Leucine-rich repeat kinase-2 (LRRK2), a gene mutated in familial and sporadic Parkinson’s disease (PD), controls multiple cellular processes important for GLIA physiology. Interestingly, emerging studies report that LRRK2 is highly expressed in oligodendrocyte precursor cells (OPCs) compared to the pathophysiology of other brain cells and oligodendrocytes (OLs) in PD. Altogether, these observations suggest crucial function(s) of LRRK2 in OPCs/Ols, which would be interesting to explore. In this study, we investigated the role of LRRK2 in OLs. We showed that LRRK2 knock-out (KO) OPC cultures displayed defects in the transition of OPCs into OLs, suggesting a role of LRRK2 in OL differentiation. Consistently, we found an alteration of myelin basic protein (MBP) striosomes in LRRK2 KO mouse brains and reduced levels of oligodendrocyte transcription factor 2 (Olig2) and Mbp in olig2:EGFP and mbp:RFP transgenic zebrafish embryos injected with lrrk2 morpholino (MO). Moreover, lrrk2 knock-down zebrafish exhibited a lower amount of nerve growth factor (Ngf) compared to control embryos, which represents a potent regulator of oligodendrogenesis and myelination. Overall, our findings indicate that LRRK2 controls OL differentiation, affecting the number of mature OLs. Full article

The central nervous system (CNS) exhibits remarkable adaptability throughout life, enabled by intricate interactions between neurons and glial cells, in particular, oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs). This adaptability is pivotal for learning and memory, with OLs and OPCs playing a crucial role in neural circuit development, synaptic modulation, and myelination dynamics. Myelination by OLs not only supports axonal conduction but also undergoes adaptive modifications in response to neuronal activity, which is vital for cognitive processing and memory functions. This review discusses how these cellular interactions and myelin dynamics are implicated in various neurocircuit diseases and disorders such as epilepsy, gliomas, and psychiatric conditions, focusing on how maladaptive changes contribute to disease pathology and influence clinical outcomes. It also covers the potential for new diagnostics and therapeutic approaches, including pharmacological strategies and emerging biomarkers in oligodendrocyte functions and myelination processes. The evidence supports a fundamental role for myelin plasticity and oligodendrocyte functionality in synchronizing neural activity and high-level cognitive functions, offering promising avenues for targeted interventions in CNS disorders. Full article

Clinical treatment options to combat Encephalopathy of Prematurity (EoP) are still lacking. We, and others, have proposed (intranasal) mesenchymal stem cells (MSCs) as a potent therapeutic strategy to boost white matter repair in the injured preterm brain. Using a double-hit mouse model of diffuse white matter injury, we previously showed that the efficacy of MSC treatment was time dependent, with a significant decrease in functional and histological improvements after the postponement of cell administration. In this follow-up study, we aimed to investigate the mechanisms underlying this loss of therapeutic efficacy. Additionally, we optimized the regenerative potential of MSCs by means of genetic engineering with the transient hypersecretion of beneficial factors, in order to prolong the treatment window. Though the cerebral expression of known chemoattractants was stable over time, the migration of MSCs to the injured brain was partially impaired. Moreover, using a primary oligodendrocyte (OL) culture, we showed that the rescue of injured OLs was reduced after delayed MSC coculture. Cocultures of modified MSCs, hypersecreting IGF1, LIF, IL11, or IL10, with primary microglia and OLs, revealed a superior treatment efficacy over naïve MSCs. Additionally, we showed that the delayed intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, improved myelination and the functional outcome in EoP mice. In conclusion, the impaired migration and regenerative capacity of intranasally applied MSCs likely underlie the observed loss of efficacy after delayed treatment. The intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, is a promising optimization strategy to prolong the window for effective MSC treatment in preterm infants with EoP. Full article

A variety of neurological and psychiatric disorders have recently been shown to be highly associated with the abnormal development and function of oligodendrocytes (OLs) and interneurons. OLs are the myelin-forming cells in the central nervous system (CNS), while interneurons are important neural types gating the function of excitatory neurons. These two types of cells are of great significance for the establishment and function of neural circuits, and they share similar developmental origins and transcriptional architectures, and interact with each other in multiple ways during development. In this review, we compare the similarities and differences in these two cell types, providing an important reference and further revealing the pathogenesis of related brain disorders. Full article

Chlorogenic acid (CGA), a polyphenol found mainly in coffee and tea, exerts antioxidant, anti-inflammatory and anti-apoptotic effects at the gastrointestinal level. However, although CGA is known to cross the blood–brain barrier (BBB), its effects on the CNS are still unknown. Oligodendrocytes (OLs), the myelin-forming cells in the CNS, are the main target in demyelinating neuroinflammatory diseases such as multiple sclerosis (MS). We evaluated the antioxidant, anti-inflammatory and anti-apoptotic roles of CGA in M03-13, an immortalized human OL cell line. We found that CGA reduces intracellular superoxide ions, mitochondrial reactive oxygen species (ROS) and NADPH oxidases (NOXs) /dual oxidase 2 (DUOX2) protein levels. The stimulation of M03-13 cells with TNFα activates the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB) pathway, leading to an increase in superoxide ion, NOXs/DUOX2 and phosphorylated extracellular regulated protein kinase (pERK) levels. In addition, tumor necrosis factor alpha (TNF-α) stimulation induces caspase 8 activation and the cleavage of poly-ADP-ribose polymerase (PARP). All these TNFα-induced effects are reversed by CGA. Furthermore, CGA induces a blockade of proliferation, driving cells to differentiation, resulting in increased mRNA levels of myelin basic protein (MBP) and proteolipid protein (PLP), which are major markers of mature OLs. Overall, these data suggest that dietary supplementation with this polyphenol could play an important beneficial role in autoimmune neuroinflammatory diseases such as MS. Full article

CHD7, an encoding ATP-dependent chromodomain helicase DNA-binding protein 7, has been identified as the causative gene involved in CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia choanae, Retardation of growth and/or development, Genital abnormalities and Ear abnormalities). Although studies in rodent models have expanded our understanding of CHD7, its role in oligodendrocyte (OL) differentiation and myelination in zebrafish is still unclear. In this study, we generated a chd7-knockout strain with CRISPR/Cas9 in zebrafish. We observed that knockout (KO) of chd7 intensely impeded the oligodendrocyte progenitor cells’ (OPCs) migration and myelin formation due to massive expression of chd7 in oilg2⁺ cells, which might provoke upregulation of the MAPK signal pathway. Thus, our study demonstrates that chd7 is critical to oligodendrocyte migration and myelination during early development in zebrafish and describes a mechanism potentially associated with CHARGE syndrome. Full article

An unmet clinical goal in demyelinating pathologies is to restore the myelin sheath prior to neural degeneration. N-acetylaspartate (NAA) is an acetylated derivative form of aspartate, abundant in the healthy brain but severely reduced during traumatic brain injury and in patients with neurodegenerative pathologies. How extracellular NAA variations impact the remyelination process and, thereby, the ability of oligodendrocytes to remyelinate axons remains unexplored. Here, we evaluated the remyelination properties of the oligodendroglial (OL) mouse cell line Oli-neuM under different concentrations of NAA using a combination of biochemical, qPCR, immunofluorescence assays, and in vitro engagement tests, at NAA doses compatible with those observed in healthy brains and during brain injury. We observed that oligodendroglia cells respond to decreasing levels of NAA by stimulating differentiation and promoting gene expression of myelin proteins in a temporally regulated manner. Low doses of NAA potently stimulate Oli-neuM to engage with synthetic axons. Furthermore, we show a concentration-dependent expression of specific histone deacetylases essential for MBP gene expression under NAA or Clobetasol treatment. These data are consistent with the idea that oligodendrocytes respond to lowering the NAA concentration by activating the remyelination process via deacetylase activation. Full article

A growing body of studies suggests that Ca²⁺ signaling controls a variety of biological processes in brain elements. Activation of L-type voltage-operated Ca²⁺ channels (VOCCs) plays a role in the development of oligodendrocyte (OL) lineage loss, and indicates that the blocking of these channels may be an effective way to inhibit OL lineage cell loss. For this study, 10.5-day-old male Sprague–Dawley rats were used to generate cerebellar tissue slices. The slice tissues were cultured and randomly allocated to one of four groups (six each) and treated as follows: Group I, (sham control); Group II, 0.1% dimethyl sulfoxide (DMSO) only (vehicle control); Group III, injury (INJ); Group IV, (INJ and treatment with NIF). The injury was simulated by exposing the slice tissues to 20 min of oxygen–glucose deprivation (OGD). At 3 days post-treatment, the survival, apoptosis, and proliferation of the OL lineages were measured and compared. Results: In the INJ group, there was a decrease in mature myelin basic protein+ OLs (MBP+ OLs) and their precursors, NG2⁺ OPCs (Nerve-glia antigen 2+ oligodendrocyte precursor cell), compared with controls. A significant elevation was observed in the NG2⁺ OPCs and apoptotic MBP⁺ OLs as confirmed by a TUNEL assay. However, the cell proliferation rate was decreased in NG2⁺ OPCs. NIF increased OL survival as measured by apoptosis rate in both OL lineages and preserved the rate of proliferation in the NG2⁺ OPCs. Conclusions: Activation of L-type VOCCs may contribute to OL pathology in association with reduced mitosis of OPCs following brain injury as a strategy to treat demyelinating diseases. Full article