Myelin Oligodendrocyte Research Articles

Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis

How neuronal signaling affects brain myelination remains poorly understood. We show dysregulated neuronal RHEB-mTORC1-DLK1 axis impairs brain myelination. Neuronal Rheb cKO impairs oligodendrocyte differentiation/myelination, with activated neuronal expression of the imprinted gene Dlk1. Neuronal Dlk1 cKO ameliorates myelination deficit in neuronal Rheb cKO mice, indicating that activated neuronal Dlk1 expression contributes to impaired myelination caused by Rheb cKO. The effect of Rheb cKO on Dlk1 expression is mediated by mTORC1; neuronal mTor cKO and Raptor cKO and pharmacological inhibition of mTORC1 recapitulate elevated neuronal Dlk1 expression. We demonstrate that both a secreted form of DLK1 and a membrane-bound DLK1 inhibit the differentiation of cultured oligodendrocyte precursor cells into oligodendrocytes expressing myelin proteins. Finally, neuronal expression of Dlk1 in transgenic mice reduces the formation of mature oligodendrocytes and myelination. This study identifies Dlk1 as an inhibitor of oligodendrocyte myelination and a mechanism linking altered neuronal signaling with oligodendrocyte dysfunction.

Pro-myelinating clemastine administration improves recording performance of chronically implanted microelectrodes and nearby neuronal health

Intracortical microelectrodes have become a useful tool in neuroprosthetic applications in the clinic and to understand neurological disorders in basic neurosciences. Many of these brain-machine interface technology applications require successful long-term implantation with high stability and sensitivity. However, the intrinsic tissue reaction caused by implantation remains a major failure mechanism causing loss of recorded signal quality over time. Oligodendrocytes remain an underappreciated intervention target to improve chronic recording performance. These cells can accelerate action potential propagation and provides direct metabolic support for neuronal health and functionality. However, implantation injury causes oligodendrocyte degeneration and leads to progressive demyelination in surrounding brain tissue. Previous work highlighted that healthy oligodendrocytes are necessary for greater electrophysiological recording performance and the prevention of neuronal silencing around implanted microelectrodes over the chronic implantation period. Thus, we hypothesize that enhancing oligodendrocyte activity with a pharmaceutical drug, Clemastine, will prevent the chronic decline of microelectrode recording performance. Electrophysiological evaluation showed that the promyelination Clemastine treatment significantly elevated the signal detectability and quality, rescued the loss of multi-unit activity, and increased functional interlaminar connectivity over 16-weeks of implantation. Additionally, post-mortem immunohistochemistry showed that increased oligodendrocyte density and myelination coincided with increased survival of both excitatory and inhibitory neurons near the implant. Overall, we showed a positive relationship between enhanced oligodendrocyte activity and neuronal health and functionality near the chronically implanted microelectrode. This study shows that therapeutic strategy that enhance oligodendrocyte activity is effective for integrating the functional device interface with brain tissue over chronic implantation period.

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.

The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain.

Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux. The absence of this protein in humans and rodents produces progressive neurodegeneration with brain iron accumulation. Astrocytes express high levels of Cp and iron efflux from these cells has been shown to be central for oligodendrocyte maturation and myelination. To explore the role of astrocytic Cp in brain development and aging we generated a specific conditional KO mouse for Cp in astrocytes (Cp cKO). Deletion of Cp in astrocytes during the first postnatal week induced hypomyelination and a significant delay in oligodendrocyte maturation. This abnormal myelin synthesis was exacerbated throughout the first two postnatal months and accompanied by a reduction in oligodendrocyte iron content, as well as an increase in brain oxidative stress. In contrast to young animals, deletion of astrocytic Cp at 8 months of age engendered iron accumulation in several brain areas and neurodegeneration in cortical regions. Aged Cp cKO mice also showed myelin loss and oxidative stress in oligodendrocytes and neurons, and at 18 months of age, developed abnormal behavioral profiles, including deficits in locomotion and short-term memory. In summary, our results demonstrate that iron efflux-mediated by astrocytic Cp-is essential for both early oligodendrocyte maturation and myelin integrity in the mature brain. Additionally, our data suggest that astrocytic Cp activity is central to prevent iron accumulation and iron-induced oxidative stress in the aging CNS.

Mature and Myelinating Oligodendrocytes Are Specifically Vulnerable to Mild Fluid Percussion Injury in Mice.

Myelin loss and oligodendrocyte death are well documented in patients with traumatic brain injury (TBI), as well as in experimental animal models after moderate-to-severe TBI. In comparison, mild TBI (mTBI) does not necessarily result in myelin loss or oligodendrocyte death, but causes structural alterations in the myelin. To gain more insight into the impact of mTBI on oligodendrocyte lineage in the adult brain, we subjected mice to mild lateral fluid percussion injury (mFPI) and characterized the early impact (1 and 3 days post-injury) on oligodendrocytes in the corpus callosum using multiple oligodendrocyte lineage markers (platelet-derived growth factor receptor [PDGFR]-α, glutathione S-transferase [GST]-π, CC1, breast carcinoma-amplified sequence 1 [BCAS1], myelin basic protein [MBP], myelin-associated glycoprotein [MAG], proteolipid protein [PLP], and FluoroMyelin™). Two regions of the corpus callosum in relation to the impact site were analyzed: areas near (focal) and anterior (distal) to the impact site. mFPI did not result in oligodendrocyte death in either the focal or distal corpus callosum, nor impact on oligodendrocyte precursors (PDGFR-α+) and GST-π+ oligodendrocyte numbers. In the focal but not distal corpus callosum, mFPI caused a decrease in CC1+ as well as BCAS1+ actively myelinating oligodendrocytes and reduced FluoroMyelin intensity without altering myelin protein expression (MBP, PLP, and MAG). Disruption in node-paranode organization and loss of Nav1.6+ nodes were observed in both the focal and distal regions, even in areas without obvious axonal damage. Altogether, our study shows regional differences in mature and myelinating oligodendrocyte in response to mFPI. Further, mFPI elicits a widespread impact on node-paranode organization that affects regions both close to and remotely located from the site of injury.

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease

The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3. As oligodendrocytes support axonal energy metabolism and neuronal health4–7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.

Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder

ObjectiveTo investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum...

Identifying specific myelopathy etiologies in the evaluation of suspected myelitis: A retrospective analysis

BackgroundMyelopathies require prompt etiologic diagnosis. We aimed to identify a specific myelopathy diagnosis in cases of suspected myelitis to highlight clinicoradiologic differences. MethodsIn this retrospective, single-centre cohort of subjects with suspected myelitis referred to London Multiple Sclerosis (MS) Clinic between 2006 and 2021, we identified those with MS and reviewed the remaining charts for etiologic diagnosis based on clinical, serologic, and imaging details. ResultsOf 333 included subjects, 318/333 (95.5%) received an etiologic diagnosis. Most (274/333, 82%) had MS or clinically isolated syndrome. Spinal cord infarction (n = 10) was the commonest non-inflammatory myelitis mimic characterized by hyperacute decline (n = 10/10, 100%), antecedent claudication (n = 2/10, 20%), axial owl/snake eye (n = 7/9, 77%) and sagittal pencillike (n = 8/9, 89%) MRI patterns, vertebral artery occlusion/stenosis (n = 4/10, 40%), and concurrent acute cerebral infarct (n = 3/9, 33%). Longitudinal lesions were frequent in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (n = 7/7, 100%) and myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD) (n = 6/7, 86%), accompanied by bright spotty (n = 5/7, 71%) and central-grey-restricted (n = 4/7, 57%) T2-lesions on axial sequences, respectively. Leptomeningeal (n = 4/4, 100%), dorsal subpial (n = 4/4, 100%) enhancement, and positive body PET/CT (n = 4/4, 100%) aided the diagnosis of sarcoidosis. Spondylotic myelopathies had chronic sensorimotor presentations (n = 4/6, 67%) with relative bladder sparing (n = 5/6, 83%), localizable to sites of disc herniation (n = 6/6, 100%). Metabolic myelopathies showed dorsal column or inverted ‘V' sign (n = 2/3, 67%) MRI T2-abnormality with B12 deficiency. ConclusionsAlthough no single feature reliably confirms or refutes a specific myelopathy diagnosis, this study highlights patterns that narrow the differential diagnosis of myelitis and facilitate early recognition of mimics.

Axonal growth inhibitors and their receptors in spinal cord injury: from biology to clinical translation.

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelin-associated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19 (that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the RhoA/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

ZFP24 drives SOX9 upregulation and protects tubular epithelial cells during acute kidney injury

SOX9 is a transcription factor that controls cell-fate determination during embryonic development and adult tissue homeostasis in multiple organs including the kidneys. SOX9 expression is low in the adult kidneys, however, stress conditions can trigger its transcriptional upregulation in tubular epithelial cells. Functionally, SOX9 plays a protective role during the early phase of acute kidney injury (AKI) and facilitates repair during the recovery phase. To identify the upstream transcriptional regulators that drive SOX9 upregulation in tubular epithelial cells, here we have used an unbiased transcription factor screening approach. Our preliminary screening and validation studies show that Zinc finger protein 24 (ZFP24) controls injury induced SOX9 upregulation in tubular epithelial cells. ZFP24, a Cys2-His2 (C2H2) zinc finger protein is essential for oligodendrocyte maturation and myelination, however its role in the kidneys or in SOX9 regulation remains unknown. We find that tubular epithelial ZFP24 gene ablation exacerbates ischemia, rhabdomyolysis, and cisplatin-associated AKI. Importantly, ZFP24 gene deletion results in suppression of SOX9 upregulation in injured tubular epithelial cells. Chromatin immunoprecipitation and promoter luciferase assays confirmed that ZFP24 binds to a specific site in both murine and human SOX9 promoter. Importantly, CRISPR/Cas9 mediated introduction of mutations in the ZFP24 binding site in the SOX9 promoter in vivo led to suppression of SOX9 upregulation during AKI. These findings identify ZFP24 as a critical stress-responsive transcription factor that protects tubular epithelial cells during AKI in part through SOX9 upregulation. The current study was supported by NIDDK 1R01DK132230 grant to N.P. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Serum Myelin Oligodendrocyte Glycoprotein and Myelin Protein Zero as Diagnostic Biomarkers in Diabetic Neuropathy

Background: Diabetic neuropathy can affect any peripheral nerve, including sensory neurons, motor neurons, and the autonomic nervous system. Therefore, diabetic neuropathy has the potential to affect essentially any organ and can affect parts of the nervous system like the optic nerve, spinal cord, and brain. In addition, chronic hyperglycemia affects Schwann cells, and more severe patterns of diabetic neuropathy in humans involve demyelization. Schwann cell destruction might cause a number of changes in the axon. study aims to evaluate serum myelin protein level as a predicting marker in the diagnosis of diabetic neuropathy and to prevent early neuropathy complications of type 2 diabetes. Subjects and methods: To achieve the purpose of the objective, this study involved 120 individuals divided into three groups. The first group included 40 healthy individuals; the second group included 40 type 2 diabetic patients with a diabetes duration of more than 5 years; and the last group included 40 type 2 diabetic patients with a diabetes duration of less than or equal to 5 years. The enzyme-linked immunesorbent assay (ELISA) system is used to detect serum MOG and MPZ. Results: both groups of type 2 diabetes patients had significant (p≤ 0.05) increases in serum myelin protein zero P0 (MPZ) and myelin oligodendrocyte glycoprotein (MOG). Conclusion: According to the results, myelin protein can be used to diagnose patients with diabetic neuropathy at an early stage. But it did not rise to the level of a biomarker due to a lack of sensitivity

It takes two to remyelinate: A bioengineered platform to study astrocyte-oligodendrocyte crosstalk and potential therapeutic targets in remyelination

The loss of the myelin sheath insulating axons is the hallmark of demyelinating diseases. These pathologies often lead to irreversible neurological impairment and patient disability. No effective therapies are currently available to promote remyelination.Several elements contribute to the inadequacy of remyelination, thus understanding the intricacies of the cellular and signaling microenvironment of the remyelination niche might help us to devise better strategies to enhance remyelination.Here, using a new in vitro rapid myelinating artificial axon system based on engineered microfibres, we investigated how reactive astrocytes influence oligodendrocyte (OL) differentiation and myelination ability. This artificial axon culture system enables the effective uncoupling of molecular cues from the biophysical properties of the axons, allowing the detailed study of the astrocyte-OL crosstalk. Oligodendrocyte precursor cells (OPCs) were cultured on poly(trimethylene carbonate-co-ε-caprolactone) copolymer electrospun microfibres that served as surrogate axons. This platform was then combined with a previously established tissue engineered glial scar model of astrocytes embedded in 1 % (w/v) alginate matrices, in which astrocyte reactive phenotype was acquired using meningeal fibroblast conditioned medium.OPCs were shown to adhere to uncoated engineered microfibres and differentiate into myelinating OL. Reactive astrocytes were found to significantly impair OL differentiation ability, after six and eight days in a co-culture system. Differentiation impairment was seen to be correlated with astrocytic miRNA release through exosomes. We found significantly reduction on the expression of pro-myelinating miRNAs (miR-219 and miR-338) and an increase in anti-myelinating miRNA (miR-125a-3p) content between reactive and quiescent astrocytes. Additionally, we show that OPC differentiation inhibition could be reverted by rescuing the activated astrocytic phenotype with ibuprofen, a chemical inhibitor of the small rhoGTPase RhoA.Overall, these findings show that modulating astrocytic function might be an interesting therapeutic avenue for demyelinating diseases. The use of these engineered microfibres as an artificial axon culture system will enable the screening for potential therapeutic agents that promote OL differentiation and myelination while providing valuable insight on the myelination/remyelination processes.

Cognitive impairment in MOGAD is associated with ADEM-like episodes and deep grey matter atrophy (S40.006)

Cognitive impairment in MOGAD is associated with ADEM-like episodes and deep grey matter atrophy (S40.006)

Association of Disease Characteristics with Utilization of Behavioral Medicine in Patients with NMOSD and MOGAD (P13-5.016)

<h3>Objective:</h3> To evaluate utilization of behavioral medicine in patients with neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD). <h3>Background:</h3> The relationship between disease characteristics, utilization of behavioral medicine, and other healthcare services has not been well-characterized in patients with NMOSD/MOGAD. <h3>Design/Methods:</h3> In this retrospective cohort study, patients with NMOSD/MOGAD confirmed by a neuroimmunology clinic with available clinical data between June 2015 and April 2022 were identified. Relevant variables were collected, including number of behavioral medicine appointments, diagnosis, number of other healthcare visits (admissions, emergency room visits, neurology appointments, outpatient physical and occupational therapy [PT/OT] visits), and number and type of relapses (brainstem, transverse myelitis, and optic neuritis). Nonparametric t-tests were performed to compare characteristics of patients who did and did not use behavioral medicine. Pearson correlations were used to explore relationships between disease characteristics and number of behavioral medicine appointments. <h3>Results:</h3> 196 patients (70.9% NMOSD [92.8% aquaporin-4 antibody positive], 29.1% MOGAD) were identified (median duration of symptoms 8.4 years, IQR [4.6, 16.4 years]). Of these, 21 patients (90.5% NMOSD, 9.5% MOGAD) attended at least one outpatient behavioral medicine appointment. These patients had more emergency room visits (median 3, IQR [1, 8]) than non-attendees (median 1, IQR [0, 2]) (p = .04). No significant difference was detected regarding number or type of relapse or utilization of other healthcare services (for all, p &gt; .05). Brainstem flares and number of PT/OT visits correlated with number of behavioral medicine appointments (r = .72 and r = .56, respectively, p &lt; .05). <h3>Conclusions:</h3> Patients with NMOSD/MOGAD who received behavioral medicine services had greater emergency room utilization than those who did not. In our cohort, nearly 1 in 8 patients attended behavioral medicine appointments. Screening for mental health disorders in neurology clinics remains critical to appropriately identify and treat NMOSD/MOGAD patients with behavioral comorbidities. <b>Disclosure:</b> An immediate family member of Dr. Swetlik has received personal compensation for serving as an employee of Pfizer. Dr. Conway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis Pharmaceuticals. Dr. Conway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Banner Life Sciences. Dr. Conway has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Miss Widmar has nothing to disclose. Dr. Kunchok has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Kunchok has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon therapeutics . Dr. Kunchok has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology. Dr. Tworek has nothing to disclose. Dr. Sullivan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol-Myers Squibb. Dr. Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Sullivan has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Dynamed. Rachel Galioto has nothing to disclose. Dr. Aboseif has a non-compensated relationship as a AAN Autoimmune Neurology Section -- Education Workgroup with AAN that is relevant to AAN interests or activities. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Abbatemarco has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech . The institution of Dr. Abbatemarco has received research support from Horizon.

Differential Early Mechanistic Frontal Lobe Responses to Choline Chloride and Soy Isoflavones in an Experimental Model of Fetal Alcohol Spectrum Disorder.

Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of neurodevelopmental defects, and white matter is a major target of ethanol neurotoxicity. Therapeutic interventions with choline or dietary soy could potentially supplement public health preventive measures. However, since soy contains abundant choline, it would be important to know if its benefits are mediated by choline or isoflavones. We compared early mechanistic responses to choline and the Daidzein+Genistein (D+G) soy isoflavones in an FASD model using frontal lobe tissue to assess oligodendrocyte function and Akt-mTOR signaling. Long Evans rat pups were binge administered 2 g/Kg of ethanol or saline (control) on postnatal days P3 and P5. P7 frontal lobe slice cultures were treated with vehicle (Veh), Choline chloride (Chol; 75 µM), or D+G (1 µM each) for 72 h without further ethanol exposures. The expression levels of myelin oligodendrocyte proteins and stress-related molecules were measured by duplex enzyme-linked immunosorbent assays (ELISAs), and mTOR signaling proteins and phosphoproteins were assessed using 11-plex magnetic bead-based ELISAs. Ethanol's main short-term effects in Veh-treated cultures were to increase GFAP and relative PTEN phosphorylation and reduce Akt phosphorylation. Chol and D+G significantly modulated the expression of oligodendrocyte myelin proteins and mediators of insulin/IGF-1-Akt-mTOR signaling in both control and ethanol-exposed cultures. In general, the responses were more robust with D+G; the main exception was that RPS6 phosphorylation was significantly increased by Chol and not D+G. The findings suggest that dietary soy, with the benefits of providing complete nutrition together with Choline, could be used to help optimize neurodevelopment in humans at risk for FASD.

Superresolution live-cell imaging reveals that the localization of TMEM106B to filopodia in oligodendrocytes is compromised by the hypomyelination-related D252N mutation.

Hypomyelination leukodystrophies constitute a group of heritable white matter disorders exhibiting defective myelin development. Initially identified as a lysosomal protein, the TMEM106B D252N mutant has recently been associated with hypomyelination. However, how lysosomal TMEM106B facilitates myelination and how the D252N mutation disrupts that process are poorly understood. We used superresolution Hessian structured illumination microscopy (Hessian-SIM) and spinning disc-confocal structured illumination microscopy (SD-SIM) to find that the wild-type TMEM106B protein is targeted to the plasma membrane, filopodia, and lysosomes in human oligodendrocytes. The D252N mutation reduces the size of lysosomes in oligodendrocytes and compromises lysosome changes upon starvation stress. Most importantly, we detected reductions in the length and number of filopodia in cells expressing the D252N mutant. PLP1 is the most abundant myelin protein that almost entirely colocalizes with TMEM106B, and coexpressing PLP1 with the D252N mutant readily rescues the lysosome and filopodia phenotypes of cells. Therefore, interactions between TMEM106B and PLP1 on the plasma membrane are essential for filopodia formation and myelination in oligodendrocytes, which may be sustained by the delivery of these proteins from lysosomes via exocytosis.

Widespread retinal hemorrhages in a patient with atypical optic neuritis

Retinal hemorrhages are rare in optic neuritis. We report a case of atypical optic neuritis with widespread retinal hemorrhages. A 30-year-old Indian woman presented with sudden painful and severe visual loss in the left eye for 3 days. Fundus examination showed minimal optic disk edema associated with intraretinal hemorrhages extending to the periphery in the left eye. On neuroimaging, long segment thickening of the intraorbital segment of the left optic nerve was appreciated with T2 hyperintensity. Serum myelin oligodendrocyte (MOG) antibodies and neuromyelitis optica (NMO) antibodies were negative. Visual acuity improved rapidly after the administration of intravenous high-dose steroids, and fundus abnormalities resolved rapidly. Retinal hemorrhages can also be present in atypical optic neuritis in the absence of severe optic disk edema. Clinicians should be mindful of the variable presentations of optic neuritis to initiate proper and timely treatment.

Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model.

Creatine supplementation during pregnancy is a promising prophylactic treatment for perinatal hypoxic brain injury. Previously, in near-term sheep we have shown that fetal creatine supplementation reduces cerebral metabolic and oxidative stress induced by acute global hypoxia. This study investigated the effects of acute hypoxia with or without fetal creatine supplementation on neuropathology in multiple brain regions. Near-term fetal sheep were administered continuous intravenous infusion of either creatine (6 mg kg-1 h-1) or isovolumetric saline from 122 to 134 days gestational age (dGA; term is approx. 145 dGA). At 131 dGA, global hypoxia was induced by a 10 min umbilical cord occlusion (UCO). Fetuses were then recovered for 72 h at which time (134 dGA) cerebral tissue was collected for either RT-qPCR or immunohistochemistry analyses. UCO resulted in mild injury to the cortical gray matter, thalamus and hippocampus, with increased cell death and astrogliosis and downregulation of genes involved in regulating injury responses, vasculature development and mitochondrial integrity. Creatine supplementation reduced astrogliosis within the corpus callosum but did not ameliorate any other gene expression or histopathological changes induced by hypoxia. Of importance, effects of creatine supplementation on gene expression irrespective of hypoxia, including increased expression of anti-apoptotic (BCL-2) and pro-inflammatory (e.g., MPO, TNFa, IL-6, IL-1β) genes, particularly in the gray matter, hippocampus, and striatum were identified. Creatine treatment also effected oligodendrocyte maturation and myelination in white matter regions. While supplementation did not rescue mild neuropathology caused by UCO, creatine did result in gene expression changes that may influence in utero cerebral development.

Exercise in Adolescence Enhances Callosal White Matter Refinement in the Female Brain in a Rat Model of Fetal Alcohol Spectrum Disorders.

A total of 1 in 20 infants born annually are exposed to alcohol prenatally, which disrupts neurodevelopment and results in several disorders categorized under the umbrella term Fetal Alcohol Spectrum Disorders (FASD). Children and adolescents affected by FASD exhibit delayed maturation of cerebral white matter, which contributes to deficits in executive function, visuospatial processing, sensory integration, and interhemispheric communication. Research using animal models of FASD have uncovered that oligoglia proliferation, differentiation, and survival are vulnerable to alcohol teratogenesis in the male brain due in part to the activation of the neuroimmune system during gestation and infancy. A comprehensive investigation of prenatal alcohol exposure on white matter development in the female brain is limited. This study demonstrated that the number of mature oligodendrocytes and the production of myelin basic protein were reduced first in the female corpus callosum following alcohol exposure in a rat model of FASD. Analysis of myelin-related genes confirmed that myelination occurs earlier in the female corpus callosum compared to their counterparts, irrespective of postnatal treatment. Moreover, dysregulated oligodendrocyte number and myelin basic protein production was observed in the male and female FASD brain in adolescence. Targeted interventions that support white matter development in FASD-affected youth are nonexistent. The capacity for an adolescent exercise intervention to upregulate corpus callosum myelination was evaluated: we discovered that volunteer exercise increases the number of mature oligodendrocytes in alcohol-exposed female rats. This study provides critical evidence that oligoglia differentiation is difficult but not impossible to induce in the female FASD brain in adolescence following a behavioral intervention.

Endothelin-1-Endothelin receptor B complex contributes to oligodendrocyte differentiation and myelin deficits during preterm white matter injury.

Preterm cerebral white matter injury (WMI), a major form of prenatal brain injury, may potentially be treated by oligodendrocyte (OL) precursor cell (OPC) transplantation. However, the defective differentiation of OPCs during WMI seriously hampers the clinical application of OPC transplantation. Thus, improving the ability of transplanted OPCs to differentiate is critical to OPC transplantation therapy for WMI. We established a hypoxia-ischemia-induced preterm WMI model in mice and screened the molecules affected by WMI using single-cell RNA sequencing. We revealed that endothelin (ET)-1 and endothelin receptor B (ETB) are a pair of signaling molecules responsible for the interaction between neurons and OPCs and that preterm WMI led to an increase in the number of ETB-positive OPCs and premyelinating OLs. Furthermore, the maturation of OLs was reduced by knocking out ETB but promoted by stimulating ET-1/ETB signaling. Our research reveals a new signaling module for neuron-OPC interaction and provides new insight for therapy targeting preterm WMI.