bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–03–06
twelve papers selected by
  1. Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation.
  2. Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex.
  3. Perfect match: mTOR inhibitors and tuberous sclerosis complex.
  4. Mammalian target of rapamycin inhibitors for the treatment of astrocytic hamartoma in tuberous sclerosis complex (TSC).
  5. Pulmonary Langerhans cell histiocystosis (PLCH) and lymphangioleiomyomatosis (LAM) have circulating cells with loss of heterozygosity of the TSC2 gene.
  6. Analysis of serum lipid parameters predicting lipid metabolic disorders in TSC-AML patients with treatment of mTOR inhibitors.
  7. mTOR signaling as a molecular target for the alleviation of Alzheimer's disease pathogenesis.
  8. A Patient Perspective on Seizure Detection and Forecasting.
  9. Hormonal Therapy for Infantile Spasms: A Systematic Review and Meta-Analysis.
  10. Activation of Liver mTORC1 Protects Against NASH via Dual Regulation of VLDL-TAG Secretion and De Novo Lipogenesis.
  11. Activation of Rictor/mTORC2 signaling acts as a pivotal strategy to protect against sensorineural hearing loss.
  12. The mechanistic target of rapamycin as a regulator of metabolic function in oligodendroglia during remyelination.
  1. Acta Neuropathol Commun. 2022 Mar 03. 10(1): 27
    Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation.
    Andy J Liu, Jay B Lusk, John Ervin, James Burke, Richard O'Brien, Shih-Hsiu J Wang.
      Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 and TSC2 genes and autosomal dominantly inherited. These mutations cause hyperactivation of the mammalian Target of Rapamycin (mTOR) pathway, leading to the development of nonmalignant masses involving various organ systems. Patients with TSC also experience neuropsychiatric symptoms collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric Disorder (TAND). Due to research advancements in TSC, patients now live well beyond the age of 50. Many experience objective impairment of memory and executive function, supported by formal neuropsychological testing, beginning in their late 40s. Biomarker analysis has described elevated levels of phosphorylated tau-181 in the cerebrospinal fluid of patients with TAND. Tau-PET imaging has also shown focal accumulation of the radiotracer flortaucipir (AV1451), suggesting that TSC may be a neurodegenerative disorder arising from accumulation of phosphorylated tau. However, the flortaucipir tracer has been reported to have significant off-target binding, preventing definitive conclusions from being drawn about the molecular etiology of neurodegeneration in TSC. Therefore, we initiated the Colocalization of AV1451 and Phosphorylated Tau in Adult brain tissue (CAPA) study. This study aimed to determine if flortaucipir is bound to phosphorylated tau in brains of patients with TSC and further sought to determine the specific tau isoform seen in TSC. Our results show that flortaucipir labels the 3R/4R isoform of phosphorylated tau, commonly seen in Alzheimer's disease. However, amyloid staining was negative in brains of adult patients with TSC. Therefore, we conclude that TAND symptoms are due to the accumulation of the phosphorylated tau isoform seen in Alzheimer's disease. This study suggests that hyperactivation of the mammalian Target of Rapamycin pathway may play a role in the amyloid-independent development of 3R/4R tau aggregation. Our findings could lead to a new era of anti-tau therapies used to treat both disorders.
    Keywords:  3R tauopathy; 4R tauopathy; Alzheimer’s disease; Phosphorylated tau; Tauopathy; Tuberous Sclerosis Complex
    DOI:  https://doi.org/10.1186/s40478-022-01330-x
  2. Epilepsy Res. 2022 Feb 18. pii: S0920-1211(22)00041-9. [Epub ahead of print]181 106890
    Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex.
    Lena H Nguyen, Steven C Leiser, Dekun Song, Daniela Brunner, Steven L Roberds, Michael Wong, Angelique Bordey.
      Tuberous sclerosis complex (TSC) is a monogenic disorder characterized by hyperactivation of the mTOR signaling pathway and developmental brain malformations leading to intractable epilepsy. Although treatment with the recently approved mTOR inhibitor, everolimus, results in clinically relevant seizure suppression in up to 40% of TSC patients, seizures remain uncontrolled in a large number of cases, underscoring the need to identify novel treatment targets. The MEK-ERK signaling pathway has been found to be aberrantly activated in TSC and inhibition of MEK-ERK activity independently of mTOR rescued neuronal dendrite overgrowth in mice modeling TSC neuropathology. Here, we evaluated the efficacy of MEK-ERK inhibition on seizures in two mouse models of TSC. We found that treatment with the MEK inhibitor PD0325901 (mirdametinib) significantly reduced seizure activity in both TSC mouse models. These findings support inhibiting MEK-ERK activity as a potential alternative strategy to treat seizures in TSC.
    Keywords:  Epilepsy; MAPK; MEK inhibitor; MEK-ERK signaling; Seizures; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.eplepsyres.2022.106890
  3. Orphanet J Rare Dis. 2022 Mar 04. 17(1): 106
    Perfect match: mTOR inhibitors and tuberous sclerosis complex.
    Cong Luo, Wen-Rui Ye, Wei Shi, Ping Yin, Chen Chen, Yun-Bo He, Min-Feng Chen, Xiong-Bin Zu, Yi Cai.
      Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that presents with diverse and complex clinical features and involves multiple human systems. TSC-related neurological abnormalities and organ dysfunction greatly affect the quality of life and can even result in death in patients with TSC. It is widely accepted that most TSC-related clinical manifestations are associated with hyperactivation of the mammalian target of rapamycin (mTOR) pathway caused by loss‑of‑function mutations in TSC1 or TSC2. Remarkable progress in basic and translational research has led to encouraging clinical advances. Although mTOR inhibitors (rapamycin/everolimus) demonstrate great potential in TSC management, two major concerns hamper their generalized application. One is the frequent manifestation of adverse events, such as stomatitis, infections, and menstrual disorders; and the other is the poor response in certain patients. Thus, indicators are required to effectively predict the efficacy of mTOR inhibitors. Herein, we have summarized the current utilization of mTOR inhibitors in the treatment of TSC and focused on their efficacy and safety, in an attempt to provide a reference to guide the treatment of TSC.
    Keywords:  Adverse events; Efficacy; Precision medicine; Tuberous sclerosis complex (TSC); mTOR inhibitors
    DOI:  https://doi.org/10.1186/s13023-022-02266-0
  4. Graefes Arch Clin Exp Ophthalmol. 2022 Mar 01.
    Mammalian target of rapamycin inhibitors for the treatment of astrocytic hamartoma in tuberous sclerosis complex (TSC).
    Ofri Vorobichik Berar, Michal Tzadok, Ofira Zloto, Iris Moroz, Idan Hecht, Anne Ampaire Musika, Omer Shlomovitz, Ido-Didi Fabian, Vicktoria Vishnevskia Dai.
       PURPOSE: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder. Fifty percent of patients with TSC will develop retinal astrocytic hamartoma (RAH). The mammalian target of rapamycin (mTOR) inhibitors interferes with the pathological mechanisms of TSC. Treatment of RAH with mTOR inhibitors has been described in only a few isolated case reports. The purpose of this study was to assess the effect of mTOR inhibitors on RAH in a small cohort of patients.
    METHODS: The medical records of all consecutive patients with ocular manifestations of TSC that were treated with mTOR inhibitors at the Sheba Medical Center from January 2014 to December 2018 were retrospectively reviewed. Data collection included demographics, medical history, ocular presentation, ocular treatment, and treatment outcome. Tumor size was assessed by a masked observer, before and after treatment. Lesion measurements were made with Heidelberg SD-OCT (HRA + OCT SPECTRALIS), and fundus photos were taken with RetCam3® (Natus, USA) and analyzed by "ImageJ" software.
    RESULTS: Eleven patients with tuberous sclerosis and astrocytic hamartoma were treated with mTOR inhibitors in the study period. Of them, 6 children (11 eyes, 20 tumors) had proper imaging of tumor size before and after treatment. The analysis included these 11 eyes. All six patients had non-ocular manifestations of TSC, including dermatologic (n = 5), neurologic (n = 5), and renal (n = 3) involvement. Ocular involvement included in five eyes (45%) tumors near the optic disc and in four eyes (37%) foveal tumors. The mean follow-up duration was 2.15 ± 1.4 years (range 10 months to 4.5 years). The average tumor base reduction in the treated group was 17.8% ± 15.9. The average maximal thickness at baseline was 414 ± 174 μm (range 152-686 μm). There was a 14% ± 7.1 reduction after treatment. None of the tumors showed evidence of growth at the final follow-up.
    CONCLUSION: The findings of this study suggest that mTOR inhibitors can reduce tumor size and that they can be considered as an optional treatment in certain conditions. This preliminary report is the first to quantitatively assess pre- and posttreatment tumor size, in young patients.
    Keywords:  Retinal astrocytic hamartoma; Tuberous sclerosis complex; mTOR inhibitors
    DOI:  https://doi.org/10.1007/s00417-022-05585-x
  5. Chest. 2022 Feb 26. pii: S0012-3692(22)00398-1. [Epub ahead of print]
    Pulmonary Langerhans cell histiocystosis (PLCH) and lymphangioleiomyomatosis (LAM) have circulating cells with loss of heterozygosity of the TSC2 gene.
    Davide Elia, Olga Torre, Chiara Vasco, Jens Geginat, Sergio Abrignani, Elisabetta Bulgheroni, Elena Carelli, Roberto Cassandro, Gustavo Pacheco-Rodriguez, Wendy K Steagall, Joel Moss, Sergio Harari.
       BACKGROUND: Lymphangioleiomyomatosis (LAM) and pulmonary Langerhans Cell Histiocytosis (PLCH) are cystic lung diseases in which a neoplastic cell is believed to be responsible for disease pathogenesis. The neoplastic LAM cell has mutations in the Tuberous Sclerosis Complex (TSC) genes, TSC1 or TSC2, whereas the neoplastic PLCH cell may have mutations in several genes, e.g., BRAF, NRAS, MAP2K1. These mutations are not specific for PLCH and they have been described in multiple cancers. TSC1 or TSC2 mutations and loss of heterozygosity (LOH) have also been described in cancers.
    RESEARCH QUESTION: Is TSC2 LOH specific to LAM or is it also found in PLCH too?
    STUDY DESIGN: We recruited LAM patients (53) and Healthy Volunteers (22) and compared the presence of cells with TSC2 LOH with PLCH patients (12). Blood and urine samples were collected for analysis.
    METHODS: Fluorescence-activated cell sorting (FACS) was used to identify subpopulations of cells from blood and urine samples. We isolated CD45-CD235a-, CD45-CD235a+, CD45+CD235a- cells from blood following density gradient separation. Cells were screened for TSC2 LOH at 5 microsatellites markers (i.e., kg8, D16S3395, D16S3024, D16S521, D16S291). We obtained four cell subpopulations from urine (i.e., CD44v6+CD9+; CD44v6+CD9-; CD44v6-CD9+; CD44v6-CD9).
    RESULTS: Using FACS, cells were isolated from blood and urine from PLCH patients that showed TSC2 LOH. Healthy volunteers did not have cells with TSC2 LOH. As a control, cells isolated from blood and urine from LAM patients gave results similar to those reported previously. These data show that TSC2 LOH is found in patients with cystic lung diseases with potential neoplastic characteristics, as well as in patients with cancer.
    INTERPRETATION: The presence of TSC2 LOH in circulating cells is not specific for LAM. The data suggest that chromosomal abnormalities affecting the TSC2 gene are found in other diseases associated with cells having cancer-like neoplastic cells.
    DOI:  https://doi.org/10.1016/j.chest.2022.02.032
  6. J Clin Pharm Ther. 2022 Mar 01.
    Analysis of serum lipid parameters predicting lipid metabolic disorders in TSC-AML patients with treatment of mTOR inhibitors.
    Wenda Wang, Zhan Wang, Yang Zhao, Xu Wang, Hanzhong Li, Yushi Zhang.
       WHAT IS KNOWN AND OBJECTIVE: Patients with tuberous sclerosis complex (TSC) demonstrate disrupted lipid homeostasis before and during treatment with mammalian target of rapamycin (mTOR) inhibitor. However, few previous reports focused on if the serum lipid status at baseline would influence lipid metabolic side-effects of mTOR inhibitors for TSC associated renal angiomyolipomas (TSC-AML). The present study was designed to evaluate the predictive function of serum lipid status at baseline for hyperlipidaemia by mTOR inhibitor treatment in TSC-AML patients.
    METHODS: The clinical data of TSC-AML patients who took mTOR inhibitors in Department of Urology of Peking Union Medical College Hospital (PUMCH) from 1 January 2014 to 1 January 2021, were retrospectively analysed. The record of lipid parameters at baseline and the highest levels of total cholesterol (TC) and triglyceride (TG) after treatment at least ≥3 months were collected. The correlation of serum lipid parameters at baseline with incidence of hyperlipidaemia during mTOR inhibitor treatment was analysed. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the ability of the serum lipid parameters in predicting hyperlipidaemia.
    RESULTS AND DISCUSSION: 19 patients experienced hyperlipidaemia and 13 patients still had normal TC and TG levels during mTOR inhibitor treatment. The levels of high-density lipoprotein cholesterol (HDL-C) (0.98 ± 0.30 mmol/L vs. 1.23 ± 0.31 mmol/L, p = 0.030), low-density lipoprotein cholesterol (LDL-C) (2.47 ± 0.69 mmol/L vs. 1.95 ± 0.53 mmol/L, p = 0.029) and apolipoprotein B (ApoB) (0.82 ± 0.21 g/L vs. 0.65 ± 0.16 g/L, p = 0.019) are higher in the patients who experienced hyperlipidaemia during mTOR inhibition therapy. TC, TG, LDL-C, ApoB and high-sensitivity C-reactive protein (hsCRP) at baseline had positive correlation with TC after treatment; ApoB at baseline had positive correlation, while HDL-C and free fat acid (FFA) at baseline had negative correlation with TG after treatment. Therefore, ApoB concentration at baseline has statistically significant correlation with both TC (p < 0.001) and TG (p = 0.012) levels after mTOR inhibitor treatment. ROC curve and AUC revealed that ApoB with a cut-off value of 0.640g/L may be the best parameter for predicting hyperlipidaemia during mTOR inhibitor treatment in TSC-AML patients. The incidence rates of hyperlipidaemia were 27.3% and 76.2% among the patients with ApoB level ≤0.640 g/L and >0.640 g/L respectively.
    WHAT IS NEW AND CONCLUSION: Some baseline serum lipid parameters could be used for predicting incidence of hyperlipidaemia during mTOR inhibition therapy in TSC-AML patients, and ApoB with 0.640 g/L as a cut-off value may be a potentially optimal indicator, which could help for diagnosis and treatment decision-making.
    Keywords:  ApoB; TSC; hyperlipidaemia; mTOR inhibitors; prediction
    DOI:  https://doi.org/10.1111/jcpt.13631
  7. Neurochem Int. 2022 Feb 23. pii: S0197-0186(22)00036-5. [Epub ahead of print]155 105311
    mTOR signaling as a molecular target for the alleviation of Alzheimer's disease pathogenesis.
    Deepthi Rapaka, Veera Raghavulu Bitra, Siva Reddy Challa, Paul C Adiukwu.
      Mechanistic/mammalian target of rapamycin (mTOR) belongs to the phosphatidylinositol kinase-related kinase (PIKK) family. mTOR signaling is required for the commencement of essential cell functions including autophagy. mTOR primarily governs cell growth in response to favourable nutrients and other growth stimuli. However, it also influences aging and other aspects of nutrient-related physiology such as protein synthesis, ribosome biogenesis, and cell proliferation in adults with very limited growth. The major processes for survival such as synaptic plasticity, memory storage and neuronal recovery involve a significant mTOR activity. mTOR dysregulation is becoming a prevalent motif in a variety of human diseases, including cancer, neurological disorders, and other metabolic syndromes. The use of rapamycin to prolong life in different animal models may be attributable to the multiple roles played by mTOR signaling in various processes involved in ageing, protein translation, autophagy, stem cell pool turnover, inflammation, and cellular senescence. mTOR activity was found to be altered in AD brains and rodent models, supporting the notion that aberrant mTOR activity is one of the key events contributing to the onset and progression of AD hallmarks This review assesses the molecular association between the mTOR signaling pathway and pathogenesis of Alzheimer's disease. The research data supporting this theme are also reviewed.
    Keywords:  Alzheimer's disease; Apoptosis; Cognition; Macroautophagy; Rapamycin; mTOR
    DOI:  https://doi.org/10.1016/j.neuint.2022.105311
  8. Front Neurol. 2022 ;13 779551
    A Patient Perspective on Seizure Detection and Forecasting.
    Aria Moss, Evan Moss, Robert Moss, Lisa Moss, Sharon Chiang, Peter Crino.
      
    Keywords:  devices; epilepsy; forecasting; patient perspective; seizure detection; seizures; tuberous sclerosis complex
    DOI:  https://doi.org/10.3389/fneur.2022.779551
  9. Front Neurol. 2022 ;13 772333
    Hormonal Therapy for Infantile Spasms: A Systematic Review and Meta-Analysis.
    Shiqi Guang, Leilei Mao, Linxiu Zhong, Fangyun Liu, Zou Pan, Fei Yin, Jing Peng.
       Objective: The limitations of adrenocorticotrophic hormone (ACTH) treatment for infantile spasms (ISs), such as high costs, limited availability, and adverse effects (AEs), make it necessary to explore whether corticosteroids are optimal alternatives. Many other compelling treatments have gone through trials due to the suboptimal effectiveness of hormonal therapy. A systematic review and meta-analysis were performed to evaluate the effectiveness and safety of hormonal therapy for patients with ISs.
    Methods: EMBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and online registers were searched through April 2021 for randomized controlled trials (RCTs).
    Results: A total of 19 RCTs (N = 1,279) were included. There was no significant difference in the effectiveness of oral corticosteroids and ACTH in electro-clinical response (risk ratio [RR] = 0.85, 95% CI 0.41-1.76). Low-dose ACTH had similar effectiveness in electro-clinical response compared to usual-dose group (RR = 0.94, 95% CI 0.60-1.47) but conferred a lower risk of AEs (RR = 1.71, 95% CI 1.08-2.71). ACTH was more beneficial in controlling spasms than vigabatrin (VGB) (RR = 1.31, 95% CI 1.05-1.64) for patients without tuberous sclerosis complex (TSC). All RCTs were connected through network meta-analysis, and we found that ketogenic diet (KD), zonisamide, methylprednisolone, or combined treatment of hormonal therapy with topiramate (TPM) or pyridoxine was not different in electro-clinical response compared to usual-dose ACTH.
    Conclusion: Our analysis showed that oral corticosteroids could be optional alternatives when ACTH is not applicable, and ACTH is more beneficial for patients without TSC. Moreover, low-dose ACTH is recommended due to comparative effectiveness but lower risk of AEs. However, due to the high heterogeneity of included patients and treatment protocols, these results must be interpreted with caution. RCTs with multicentric involvement and larger sample size are needed for solid evaluation of other alternative treatments.
    Keywords:  ACTH; corticosteroids; hormonal therapy; infantile spasms; west syndrome
    DOI:  https://doi.org/10.3389/fneur.2022.772333
  10. Cell Mol Gastroenterol Hepatol. 2022 Feb 28. pii: S2352-345X(22)00042-X. [Epub ahead of print]
    Activation of Liver mTORC1 Protects Against NASH via Dual Regulation of VLDL-TAG Secretion and De Novo Lipogenesis.
    Kahealani Uehara, Jaimarie Sostre-Colón, Matthew Gavin, Dominic Santoleri, Kelly-Ann Leonard, René L Jacobs, Paul M Titchenell.
       BACKGROUND & AIMS: Dysregulation of liver lipid metabolism is associated with the development and progression of non-alcoholic fatty liver disease (NAFLD), a spectrum of liver diseases including non-alcoholic steatohepatitis (NASH). In the liver, insulin controls lipid homeostasis by increasing triglyceride (TAG) synthesis, suppressing fatty acid oxidation, and enhancing TAG export via very low-density lipoproteins (VLDL). Downstream of insulin signaling, the mechanistic target of rapamycin complex 1 (mTORC1), is a key regulator of lipid metabolism. Here, we define the role of mTORC1 activity in mouse models of NASH and investigate the mTORC1-dependent mechanisms responsible for protection against liver damage in NASH.
    METHODS: Utilizing two rodent NASH-promoting diets, we demonstrate that hepatic mTORC1 activity was reduced in mice with NASH, whereas under conditions of insulin resistance and benign fatty liver, mTORC1 activity was elevated. To test the beneficial effects of hepatic mTORC1 activation in mouse models of NASH, we employed an acute, liver-specific knockout model of TSC1 (L-TSC-KO), a negative regulator of mTORC1.
    RESULTS: L-TSC-KO mice are protected from and have improved markers of NASH including reduced steatosis, decreased circulating transaminases, and reduced expression of inflammation and fibrosis genes. Mechanistically, protection from hepatic inflammation and fibrosis by constitutive mTORC1 occurred via promotion of the phosphatidylcholine synthesizing enzyme, CCTα, and enhanced VLDL-TAG export. Additionally, activation of mTORC1 protected from hepatic steatosis via negative feedback of the mTORC2-AKT-FOXO-SREBP1c lipogenesis axis.
    CONCLUSIONS: Collectively, this study identifies a protective role for mTORC1 signaling in the initiation and progression of NASH in mice via dual control of lipid export and synthesis.
    Keywords:  CCTα; FOXO1; insulin; non-alcoholic fatty liver disease; phosphatidylcholine
    DOI:  https://doi.org/10.1016/j.jcmgh.2022.02.015
  11. Proc Natl Acad Sci U S A. 2022 Mar 08. 119(10): e2107357119
    Activation of Rictor/mTORC2 signaling acts as a pivotal strategy to protect against sensorineural hearing loss.
    Xiaolong Fu, Peipei Li, Linqing Zhang, Yuning Song, Yachun An, Aizhen Zhang, Wenwen Liu, Chao Ye, Yuan Zhang, Rongyu Yue, Xiaoyang Sun, Renjie Chai, Haibo Wang, Jiangang Gao.
      Significance The mechanistic target of rapamycin (mTOR) plays a central role in growth, metabolism, and aging. It is assembled into two multiprotein complexes, namely, mTORC1 and mTORC2. We previously demonstrated the efficacy of sirolimus in ARHL in mice by decreasing mTORC1. However, the aspect of mTORC2 regulation in the cochlea is poorly characterized. Herein, based on pharmacological and genetic interventions, we found that a high dose of sirolimus resulted in severe hearing loss by reducing the mTORC2/AKT signaling pathway in the cochlea. Furthermore, selective activation of mTORC2 could protect against hearing loss induced by acoustic trauma and cisplatin-induced ototoxicity. Hence, the therapeutic activation of mTORC2 in conjunction with decreasing mTORC1 might represent a promising and effective strategy in preventing hearing loss.
    Keywords:  hair cells; hearing; mTORC2
    DOI:  https://doi.org/10.1073/pnas.2107357119
  12. Curr Opin Pharmacol. 2022 Mar 01. pii: S1471-4892(22)00019-4. [Epub ahead of print]63 102193
    The mechanistic target of rapamycin as a regulator of metabolic function in oligodendroglia during remyelination.
    Marie L Mather, Marisa A Jeffries, Teresa L Wood.
      Despite evidence for prominent metabolic dysfunction within multiple sclerosis (MS) lesions, the mechanisms controlling metabolic shifts in oligodendroglia are poorly understood. The cuprizone model of demyelination and remyelination is a valuable tool for assessing metabolic insult during oligodendrocyte death and myelin degradation, closely resembling the distal oligodendrogliopathy seen in Pattern III MS lesions. In this review we discuss how metabolic processes in oligodendrocytes are disrupted in both MS and the cuprizone model, as well as the evidence for mechanistic target of rapamycin (mTOR) signaling as a key regulator of oligodendroglial metabolic function and efficient remyelination.
    DOI:  https://doi.org/10.1016/j.coph.2022.102193
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