Oligodendrocyte Lineage Research Articles

Recombinant Erythropoietin Induces Oligodendrocyte Progenitor Cell Proliferation After Traumatic Brain Injury and Delayed Hypoxemia

Traumatic brain injury (TBI) can result in axonal loss and demyelination, leading to persistent damage in the white matter. Demyelinated axons are vulnerable to pathologies related to an abnormal myelin structure that expose neurons to further damage. Oligodendrocyte progenitor cells (OPCs) mediate remyelination after recruitment to the injury site. Often this process is inefficient due to inadequate OPC proliferation. To date, no effective treatments are currently available to stimulate OPC proliferation in TBI. Recombinant human erythropoietin (rhEPO) is a pleiotropic neuroprotective cytokine, and its receptor is present in all stages of oligodendroglial lineage cell differentiation. Therefore, we hypothesized that rhEPO administration would enhance remyelination after TBI through the modulation of OPC response. Utilizing a murine model of controlled cortical impact and a primary OPC culture in vitro model, we characterized the impact of rhEPO on remyelination and proliferation of oligodendrocyte lineage cells. Myelin black gold II staining of the peri-contusional corpus callosum revealed an increase in myelinated area in association with an increase in BrdU-positive oligodendrocytes in injured mice treated with rhEPO. Furthermore, morphological analysis of OPCs showed a decrease in process length in rhEPO-treated animals. RhEPO treatment increased OPC proliferation after in vitro CSPG exposure. Erythropoietin receptor (EPOr) gene knockdown using siRNA prevented rhEPO-induced OPC proliferation, demonstrating that the rhEPO effect on OPC response is EPOr activation dependent. Together, our findings demonstrate that rhEPO administration may promote myelination by increasing oligodendrocyte lineage cell proliferation after TBI.

Aerobic exercise attenuates abnormal myelination and oligodendrocyte differentiation in 3xTg-AD mice

Pathological features of Alzheimer's Disease (AD) include alterations in the structure and function of neurons as well as of myelin sheaths. Accumulated evidence shows that aerobic type of exercise can enhance neuroplasticity in mouse models of AD. However, whether and how aerobic exercise can affect myelin sheath repair and neuroprotection in the AD models remains unclear. In this study we tested the hypotheses that 1) myelin structural alterations in 3xTg-AD mice would be related to abnormalities in oligodendrocyte lineage cells, resulting in impaired learning and memory, and 2) a 6-month aerobic exercise intervention would have beneficial effects on such alterations. Two-month-old male 3xTg-AD mice were randomly assigned to a control (AC) or an exercise (AE) group, and age-matched male C57BL/6;129 mice were also randomly assigned to a normal control (NC) or an exercise (NE) group, with n = 12 in each group. Mice in the exercise groups were trained on a motor-drive treadmill, 60 min per day, 5 days per week for 6 months. Cognitive function was assessed at the end of the intervention period. Then, brain specimens were obtained for assessments of morphological and oligodendrocyte lineage cell changes. The results of electron microscopy showed that myelin ultrastructure demonstrated a higher percentage of loose and granulated myelin sheath around axons in the temporal lobe in the AC, as compared with the NC group, along with greater cognitive dysfunction at 8-months of age. These differences were accompanied by significantly greater myelin basic protein (MBP) expression and less neuron-glial antigen-2 (NG2) protein and mRNA levels in the AC, compared to the NC. However, there were no significant between-group differences in the G-ratio (the ratio of axon diameter to axon plus myelin sheath diameter) and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) protein and mRNA levels. The aerobic exercise ameliorated cognitive deterioration and appeared to keep components of myelin sheath and oligodendrocyte precursor cells stabilized, resulting in a decrease in the percentage of loose and granulated myelin sheath and MBP protein, and an increase in NG2 protein and mRNA levels in the AE group. Therefore, the 6-month exercise intervention demonstrated beneficial effects on myelin lesions, abnormal differentiation of oligodendrocytes and general brain function in the 3xTg-AD mice, providing further insights into the role of aerobic exercise in management of neurodegeneration in AD by maintaining intact myelination.

YAP and TAZ regulate remyelination in the central nervous system.

Myelinating cells are sensitive to mechanical stimuli from their extracellular matrix. Ablation of YAP and TAZ mechanotransducers in Schwann cells abolishes the axon-Schwann cell recognition, myelination, and remyelination in the peripheral nervous system. It was unknown if YAP and TAZ are also required for myelination and remyelination in the central nervous system. Here we define the importance of oligodendrocyte (OL) YAP and TAZ in vivo, by specific deletion in oligodendroglial cells in adult OLs during myelin repair. Blocking YAP and TAZ expression in OL lineage cells did not affect animal viability or any major defects on OL maturation and myelination. However, using a mouse model of demyelination/remyelination, we demonstrate that YAP and TAZ modulate the capacity of OLs to remyelinate axons, particularly during the early stage of the repair process, when OL proliferation is most important. These results indicate that YAP and TAZ signaling is necessary for effective remyelination of the mouse brain.

Conditional Deletion of Foxg1 Delayed Myelination during Early Postnatal Brain Development.

FOXG1 (forkhead box G1) syndrome is a neurodevelopmental disorder caused by variants in the Foxg1 gene that affect brain structure and function. Individuals affected by FOXG1 syndrome frequently exhibit delayed myelination in neuroimaging studies, which may impair the rapid conduction of nerve impulses. To date, the specific effects of FOXG1 on oligodendrocyte lineage progression and myelination during early postnatal development remain unclear. Here, we investigated the effects of Foxg1 deficiency on myelin development in the mouse brain by conditional deletion of Foxg1 in neural progenitors using NestinCreER;Foxg1fl/fl mice and tamoxifen induction at postnatal day 0 (P0). We found that Foxg1 deficiency resulted in a transient delay in myelination, evidenced by decreased myelin formation within the first two weeks after birth, but ultimately recovered to the control levels by P30. We also found that Foxg1 deletion prevented the timely attenuation of platelet-derived growth factor receptor alpha (PDGFRα) signaling and reduced the cell cycle exit of oligodendrocyte precursor cells (OPCs), leading to their excessive proliferation and delayed maturation. Additionally, Foxg1 deletion increased the expression of Hes5, a myelin formation inhibitor, as well as Olig2 and Sox10, two promoters of OPC differentiation. Our results reveal the important role of Foxg1 in myelin development and provide new clues for further exploring the pathological mechanisms of FOXG1 syndrome.

Distinct requirements for Tcf3 and Tcf12 during oligodendrocyte development in the mouse telencephalon

BackgroundE-proteins encoded by Tcf3, Tcf4, and Tcf12 are class I basic helix-loop-helix (bHLH) transcription factors (TFs) that are thought to be widely expressed during development. However, their function in the developing brain, specifically in the telencephalon remains an active area of research. Our study examines for the first time if combined loss of two E-proteins (Tcf3 and Tcf12) influence distinct cell fates and oligodendrocyte development in the mouse telencephalon.MethodsWe generated Tcf3/12 double conditional knockouts (dcKOs) using Olig2Cre/+ or Olig1Cre/+ to overcome compensatory mechanisms between E-proteins and to understand the specific requirement for Tcf3 and Tcf12 in the ventral telencephalon and during oligodendrogenesis. We utilized a combination of in situ hybridization, immunohistochemistry, and immunofluorescence to address development of the telencephalon and oligodendrogenesis at embryonic and postnatal stages in Tcf3/12 dcKOs.ResultsWe show that the E-proteins Tcf3 and Tcf12 are expressed in progenitors of the embryonic telencephalon and throughout the oligodendrocyte lineage in the postnatal brain. Tcf3/12 dcKOs showed transient defects in progenitor cells with an enlarged medial ganglionic eminence (MGE) region which correlated with reduced generation of embryonic oligodendrocyte progenitor cells (OPCs) and increased expression of MGE interneuron genes. Postnatal Tcf3/12 dcKOs showed a recovery of OPCs but displayed a sustained reduction in mature oligodendrocytes (OLs). Interestingly, Tcf4 remained expressed in the dcKOs suggesting that it cannot compensate for the loss of Tcf3 and Tcf12. Generation of Tcf3/12 dcKOs with Olig1Cre/+ avoided the MGE morphology defect caused by Olig2Cre/+ but dcKOs still exhibited reduced embryonic OPCs and subsequent reduction in postnatal OLs.ConclusionOur data reveal that Tcf3 and Tcf12 play a role in controlling OPC versus cortical interneuron cell fate decisions in MGE progenitors in addition to playing roles in the generation of embryonic OPCs and differentiation of postnatal OLs in the oligodendrocyte lineage.

Human iPSC-derived endothelial cells promote CNS remyelination via BDNF and mTORC1 pathway.

Damage of myelin is a component of many diseases in the central nervous system (CNS). The activation and maturation of the quiescent oligodendrocyte progenitor cells (OPCs) are the crucial cellular processes for CNS remyelination, which is influenced by neuroinflammation in the lesion microenvironment. Endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) have shown promise in restoring function in various preclinical animal models. Here we ask whether and whether transplantation of hiPSC-ECs could benefit remyelination in a mouse model of CNS demyelination. Our results show that in vitro, hiPSC-ECs increase OPC proliferation, migration and differentiation via secreted soluble factors including brain-derived neurotrophic factor (BDNF). hiPSC-ECs also promote the survival of oligodendrocyte lineage cells in vitro and in vivo. Transplantation of hiPSC-ECs into a toxin-induced demyelination lesion in mouse corpus callosum (CC) leads to increased density of oligodendrocyte lineage cells and level of myelin in demyelinated area, correlated with a decreased neuroinflammation and an increased proportion of pro-regenerative M2 phenotype in microglia/macrophages. The hiPSC-EC-exposed oligodendrocyte lineage cells showed significant increase in the level of phosphorylated S6 ribosomal protein (pS6) both in vitro and in vivo, indicating an involvement of mTORC1 pathway. These results suggest that hiPSC-ECs may benefit myelin protection and regeneration which providing a potential source of cell therapy for a wide range of diseases and injuries associated with myelin damage.

Axo-glial interactions between midbrain dopamine neurons and oligodendrocyte lineage cells in the anterior corpus callosum

Oligodendrocyte progenitor cells (OPCs) receive synaptic innervation from glutamatergic and GABAergic axons and can be dynamically regulated by neural activity, resulting in activity-dependent changes in patterns of axon myelination. However, it remains unclear to what extent other types of neurons may innervate OPCs. Here, we provide evidence implicating midbrain dopamine neurons in the innervation of oligodendrocyte lineage cells in the anterior corpus callosum and nearby white matter tracts of male and female adult mice. Dopaminergic axon terminals were identified in the corpus callosum of DAT-Cre mice after injection of an eYFP reporter virus into the midbrain. Furthermore, fast-scan cyclic voltammetry revealed monoaminergic transients in the anterior corpus callosum, consistent with the anatomical findings. Using RNAscope, we further demonstrate that ~ 40% of Olig2 + /Pdfgra + cells and ~ 20% of Olig2 + /Pdgfra- cells in the anterior corpus callosum express Drd1 and Drd2 transcripts. These results suggest that oligodendrocyte lineage cells may respond to dopamine released from midbrain dopamine axons, which could affect myelination. Together, this work broadens our understanding of neuron-glia interactions with important implications for myelin plasticity by identifying midbrain dopamine axons as a potential regulator of corpus callosal oligodendrocyte lineage cells.

Notch Signaling Plays a Dual Role in Regulating the Neuron-to-Oligodendrocyte Switch in the Developing Dorsal Forebrain.

Neural progenitor cells in the developing dorsal forebrain generate excitatory neurons followed by oligodendrocytes (OLs) and astrocytes. However, the specific mechanisms that regulate the timing of this neuron-glia switch are not fully understood. In this study, we show that the proper balance of Notch signaling in dorsal forebrain progenitors is required to generate oligodendrocytes during late stages of embryonic development. Using ex vivo and in utero approaches in mouse embryos of both sexes, we found that Notch inhibition reduced the number of oligodendrocyte lineage cells in the dorsal pallium. However, Notch overactivation also prevented oligodendrogenesis and maintained a progenitor state. These results point toward a dual role for Notch signaling in both promoting and inhibiting oligodendrogenesis, which must be fine-tuned to generate oligodendrocyte lineage cells at the right time and in the right numbers. We further identified the canonical Notch downstream factors HES1 and HES5 as negative regulators in this process. CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-mediated knockdown of Hes1 and Hes5 caused increased expression of the pro-oligodendrocyte factor ASCL1 and led to precocious oligodendrogenesis. Conversely, combining Notch overactivation with ASCL1 overexpression robustly promoted oligodendrogenesis, indicating a separate mechanism of Notch that operates synergistically with ASCL1 to specify an oligodendrocyte fate. We propose a model in which Notch signaling works together with ASCL1 to specify progenitors toward the oligodendrocyte lineage but also maintains a progenitor state through Hes-dependent repression of Ascl1 so that oligodendrocytes are not made too early, thus contributing to the precise timing of the neuron-glia switch.SIGNIFICANCE STATEMENT Neural progenitors make oligodendrocytes after neurogenesis starts to wind down, but the mechanisms that control the timing of this switch are poorly understood. In this study, we identify Notch signaling as a critical pathway that regulates the balance between progenitor maintenance and oligodendrogenesis. Notch signaling is required for the oligodendrocyte fate, but elevated Notch signaling prevents oligodendrogenesis and maintains a progenitor state. We provide evidence that these opposing functions are controlled by different mechanisms. Before the switch, Notch signaling through Hes factors represses oligodendrogenesis. Later, Notch signaling through an unknown mechanism promotes oligodendrogenesis synergistically with the transcription factor ASCL1. Our study underscores the complexity of Notch and reveals its importance in regulating the timing and numbers of oligodendrocyte production.

Cleavage of VAMP2/3 Affects Oligodendrocyte Lineage Development in the Developing Mouse Spinal Cord.

In the developing and adult CNS, new oligodendrocytes (OLs) are generated from a population of cells known as oligodendrocyte precursor cells (OPCs). As they begin to differentiate, OPCs undergo a series of highly regulated changes to morphology, gene expression, and membrane organization. This stage represents a critical bottleneck in oligodendrogliogenesis, and the regulatory program that guides it is still not fully understood. Here, we show that in vivo toxin-mediated cleavage of the vesicle associated SNARE proteins VAMP2/3 in the OL lineage of both male and female mice impairs the ability of early OLs to mature into functional, myelinating OLs. In the developing mouse spinal cord, many VAMP2/3-cleaved OLs appeared to stall in the premyelinating, early OL stage, resulting in an overall loss of both myelin density and OL number. The Src kinase Fyn, a key regulator of oligodendrogliogenesis and myelination, is highly expressed among premyelinating OLs, but its expression decreases as OLs mature. We found that OLs with cleaved VAMP2/3 in the spinal cord white matter showed significantly higher expression of Fyn compared with neighboring control cells, potentially because of an extended premyelinating stage. Overall, our results show that functional VAMP2/3 in OL lineage cells is essential for proper myelin formation and plays a major role in controlling the maturation and terminal differentiation of premyelinating OLs.SIGNIFICANCE STATEMENT The production of mature oligodendrocytes (OLs) is essential for CNS myelination during development, myelin remodeling in adulthood, and remyelination following injury or in demyelinating disease. Before myelin sheath formation, newly formed OLs undergo a series of highly regulated changes during a stage of their development known as the premyelinating, or early OL stage. This stage acts as a critical checkpoint in OL development, and much is still unknown about the dynamic regulatory processes involved. In this study, we show that VAMP2/3, SNARE proteins involved in vesicular trafficking and secretion play an essential role in regulating premyelinating OL development and are required for healthy myelination in the developing mouse spinal cord.

Nicotinamide enhances myelin production after demyelination through reduction of astrogliosis and microgliosis.

Caloric restriction is the chronic reduction of total caloric intake without malnutrition and has attracted a lot of attention as, among multiple other effects, it attenuates demyelination and stimulates remyelination. In this study we have evaluated the effect of nicotinamide (NAM), a well-known caloric restriction mimetic, on myelin production upon demyelinating conditions. NAM is the derivative of nicotinic acid (vitamin B3) and a precursor of nicotinamide adenine dinucleotide (NAD+), a ubiquitous metabolic cofactor. Here, we use cortical slices ex vivo subjected to demyelination or cultured upon normal conditions, a lysolecithin (LPC)-induced focal demyelination mouse model as well as primary glial cultures. Our data show that NAM enhances both myelination and remyelination ex vivo, while it also induces myelin production after LPC-induced focal demyelination ex vivo and in vivo. The increased myelin production is accompanied by reduction in both astrogliosis and microgliosis in vivo. There is no direct effect of NAM on the oligodendrocyte lineage, as no differences are observed in oligodendrocyte precursor cell proliferation or differentiation or in the number of mature oligodendrocytes. On the other hand, NAM affects both microglia and astrocytes as it decreases the population of M1-activated microglia, while reducing the pro-inflammatory phenotype of astrocytes as assayed by the reduction of TNF-α. Overall, we show that the increased myelin production that follows NAM treatment in vivo is accompanied by a decrease in both astrocyte and microglia accumulation at the lesion site. Our data indicate that NAM influences astrocytes and microglia directly, in favor of the remyelination process by promoting a less inflammatory environment.

Single-cell analysis of spinal cord injury reveals functional heterogeneity of oligodendrocyte lineage cells

Spinal cord injury (SCI) is a traumatic condition that causes myelin destruction and neuronal death, making it challenging to reverse. In spinal cord tissue, oligodendrocyte progenitor cells and oligodendrocytes are essential for maintaining myelin morphology and axon regeneration. The decrease in oligodendrocyte lineage cells after SCI is a major factor contributing to the difficulty in restoring spinal cord function. However, there is still a lack of research on the status and intercellular communication between oligodendrocyte lineage cells after injury. The development of single-cell sequencing technology has enabled researchers to obtain highly accurate cellular transcriptional information, facilitating detailed studies of cellular subpopulations. This study delved into the cellular heterogeneity of oligodendrocyte lineage cells using a single-cell transcriptomic approach to uncover functional changes and cellular interactions during different time points after SCI. Our findings highlighted the critical roles of Psap (Prosaposin)/Gpr37l1 and Psap/Gpr37 ligand-receptor pairs among oligodendrocyte lineage cells. Furthermore, we predicted the transcription factors that may play a key regulatory role. We demonstrated for the first time that Junb acts almost exclusively in mature oligodendrocytes, which provides a potential target for the study of oligodendrocyte transcriptional mechanisms.

Mapping pediatric brain tumors to their origins in the developing cerebellum.

Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the 3 most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas. We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176 645 cells as a reference for an in-depth comparison to 4416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques. We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study. Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar "lineage of origin."

Dynamic changes of oligodendrogenesis in neonatal rats with hypoxic-ischemic white matter injury

BackgroundWhite matter injury (WMI) is an important type of preterm brain injury, which may result in severe neurological sequelae and lack of effective treatments. It is ascertained that selective vulnerability of oligodendrocytes is closely related to the WMI in preterm infants. But the alteration of the endogenous oligodendrogenesis over long time after hypoxic-ischemic WMI is still not clearly elucidated. MethodsWe adopted an animal model of hypoxic-ischemic WMI in 3-day-old neonatal Sprague-Dawley rats. Immunofluorescence staining and western blotting were used to detect dynamic changes of oligodendrogenesis in the white matter region on postoperative day (POD) 1, 3, 7, 14, 28, 56 and 84. ResultsIn the sham group, the oligodendrocyte lineage in the white matter reached a developmental peak from POD 3 to 14. The proliferation and development of oligodendrocyte precursor cells (OPCs) occurred primarily within POD 14. The number of mature oligodendrocytes showed an upward trend and a dynamic change in proliferation over time. While in the WMI group, the oligodendrocyte lineage was upregulated on POD1 and 3 but downregulated on POD 7 and 14. The proliferation of OPCs increased on POD 1 and decreased on POD 3 and 7, with the total number of OPCs significantly reduced from POD 3 to 14. The number of mature oligodendrocytes decreased from POD 3 to 28, and return to the level of the sham group on POD 56 and 84, whereas the MBP expression was still significantly downregulated on POD 56 and 84. ConclusionsHypoxia-ischemia can have a long-term dynamic effect on the endogenous oligodendrogenesis of neonatal rat brain white matter. The proliferation of OPCs was promoted on POD 1 but inhibited from POD 3 to 14, which may be an early intervention target to improve oligodendrogenesis. The number of mature oligodendrocytes recover to the normal on POD 56 and 84 but the myelination is still blocked, which suggests it is essential to promote the maturation of oligodendrocyte and its function recovery at the same time within POD 28. Such efforts will provide the opportunity to test new interventions in pre-clinical studies for their promising clinical application.

Evaluation of BCAS1-positive immature oligodendrocytes after cerebral ischemic stroke and SVD

Ischemic cerebrovascular disease is an important cause of physical disability and dementia. Oligodendrocytes (OLGs), which differentiate from oligodendrocyte precursor cells (OPCs), are crucial for remyelination of the damaged brain and functional recovery. Breast carcinoma amplified sequence 1 (BCAS1) has recently been shown to be highly expressed in newly formed pre-myelinating oligodendrocytes (pre-mOLGs), while its expression level is reduced in mature OLGs. In this study, we analyzed BCAS1 expression by immunohistochemical analysis of human post-mortem brain tissue from six stroke patients (death within 2 months after stroke onset) and eight small vessel disease (SVD) patients. Control post-mortem brain tissue was from eight age-matched patients without any obvious central nervous system (CNS) pathology. The Olig2 expression in the area corresponding to the same section of the BCAS1-stained slice was analyzed to determine the total oligodendrocyte lineage. The percentage of differentiating OPCs in the oligodendrocyte lineage was calculated as the ratio of BCAS1+ to Olig2+ cells (BCAS1+/Olig2+). The stroke and SVD cases showed demyelination with decreased expression of myelin basic protein (MBP, a mature OLG marker). The stroke cases showed significantly increased numbers of early-stage BCAS1+ cells with an immature morphology and Olig2+ cells (pan-oligodendrocyte lineages) in the peri-infarct areas in both the cortex and white matter, but showed no increase in the number of late-stage BCAS1+ cells with a mature morphology. In contrast, the SVD cases showed no significant increase in Olig2+ and BCAS1+ cells. These results indicated that remyelination dysfunction could be attributed to insufficient maturation of OPCs in stroke and impaired recruitment of OPCs in SVD.

Role of MeCP2 in oligodendrocyte lineage cells in Rett syndrome: review and inference

Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Neuronal damage is the main factor contributing to RTT, and the loss of MeCP2 function can result in reduced neuronal somas size, decreased dendritic abundance, and impaired neuronal function. While specific restoration of MeCP2 expression in neurons has been reported to partially rescue the behavioral phenotype and prolong the lifespan of mice, it cannot provide a complete cure. Therefore, other cells may be involved in the development of RTT. Although imaging and autopsy findings have revealed decreased white matter volume and corpus callosum thickness in RTT patients, the mechanisms underlying the development of white matter abnormalities remain unclear. These abnormalities are predominantly caused by damage to mature oligodendrocytes. This review provides an overview of the proliferation, differentiation, and function of oligodendrocyte lineage cells and elucidates the role of MeCP2 in these cells.

The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells

The intracellular cholesterol transporter NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann–Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. Here, we use single-nucleus RNA-seq on the forebrain of Npc1−/− mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1−/− oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1−/− oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1−/− mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention.

Renewal of oligodendrocyte lineage reverses dysmyelination and CNS neurodegeneration through corrected N-acetylaspartate metabolism.

Myelinating oligodendrocytes are essential for neuronal communication and homeostasis of the central nervous system (CNS). One of the most abundant molecules in the mammalian CNS is N-acetylaspartate (NAA), which is catabolized into L-aspartate and acetate by the enzyme aspartoacylase (ASPA) in oligodendrocytes. The resulting acetate moiety is thought to contribute to myelin lipid synthesis. In addition, affected NAA metabolism has been implicated in several neurological disorders, including leukodystrophies and demyelinating diseases such as multiple sclerosis. Genetic disruption of ASPA function causes Canavan disease, which is hallmarked by increased NAA levels, myelin and neuronal loss, large vacuole formation in the CNS, and early death in childhood. Although NAA's direct role in the CNS is inconclusive, in peripheral adipose tissue, NAA-derived acetate has been found to modify histones, a mechanism known to be involved in epigenetic regulation of cell differentiation. We hypothesize that a lack of cellular differentiation in the brain contributes to the disruption of myelination and neurodegeneration in diseases with altered NAA metabolism, such as Canavan disease. Our study demonstrates that loss of functional Aspa in mice disrupts myelination and shifts the transcriptional expression of neuronal and oligodendrocyte markers towards less differentiated stages in a spatiotemporal manner. Upon re-expression of ASPA, these oligodendrocyte and neuronal lineage markers are either improved or normalized, suggesting that NAA breakdown by Aspa plays an essential role in the maturation of neurons and oligodendrocytes. Also, this effect of ASPA re-expression is blunted in old mice, potentially due to limited ability of neuronal, rather than oligodendrocyte, recovery.

Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses.

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

Novel insights into brain lipid metabolism in Alzheimer's disease: Oligodendrocytes and white matter abnormalities.

Alzheimer's disease (AD) is the most common cause of dementia. A genome-wide association study has shown that several AD risk genes are involved in lipid metabolism. Additionally, epidemiological studies have indicated that the levels of several lipid species are altered in the AD brain. Therefore, lipid metabolism is likely changed in the AD brain, and these alterations might be associated with an exacerbation of AD pathology. Oligodendrocytes are glial cells that produce the myelin sheath, which is a lipid-rich insulator. Dysfunctions of the myelin sheath have been linked to white matter abnormalities observed in the AD brain. Here, we review the lipid composition and metabolism in the brain and myelin and the association between lipidic alterations and AD pathology. We also present the abnormalities in oligodendrocyte lineage cells and white matter observed in AD. Additionally, we discuss metabolic disorders, including obesity, as AD risk factors and the effects of obesity and dietary intake of lipids on the brain.

Evidence That DDR1 Promotes Oligodendrocyte Differentiation during Development and Myelin Repair after Injury.

Oligodendrocytes generate myelin sheaths vital for the formation, health, and function of the central nervous system. Mounting evidence suggests that receptor tyrosine kinases (RTKs) are crucial for oligodendrocyte differentiation and myelination in the CNS. It was recently reported that discoidin domain receptor 1 (Ddr1), a collagen-activated RTK, is expressed in oligodendrocyte lineage. However, its specific expression stage and functional role in oligodendrocyte development in the CNS remain to be determined. In this study, we report that Ddr1 is selectively upregulated in newly differentiated oligodendrocytes in the early postnatal CNS and regulates oligodendrocyte differentiation and myelination. Ddr1 knock-out mice of both sexes displayed compromised axonal myelination and apparent motor dysfunction. Ddr1 deficiency alerted the ERK pathway, but not the AKT pathway in the CNS. In addition, Ddr1 function is important for myelin repair after lysolecithin-induced demyelination. Taken together, the current study described, for the first time, the role of Ddr1 in myelin development and repair in the CNS, providing a novel molecule target for the treatment of demyelinating diseases.