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1.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675255

RESUMO

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor expressed in epithelial cells from different tissues in which collagen binding activates pleiotropic functions. In the brain, DDR1 is mainly expressed in oligodendrocytes (OLs), the function of which is unclear. Whether collagen can activate DDR1 in OLs has not been studied. Here, we assessed the expression of DDR1 during in vitro OL differentiation, including collagen IV incubation, and the capability of collagen IV to induce DDR1 phosphorylation. Experiments were performed using two in vitro models of OL differentiation: OLs derived from adult rat neural stem cells (NSCs) and the HOG16 human oligodendroglial cell line. Immunocytofluorescence, western blotting, and ELISA were performed to analyze these questions. The differentiation of OLs from NSCs was addressed using oligodendrocyte transcription factor 2 (Olig2) and myelin basic protein (MBP). In HOG16 OLs, collagen IV induced DDR1 phosphorylation through slow and sustained kinetics. In NSC-derived OLs, DDR1 was found in a high proportion of differentiating cells (MBP+/Olig2+), but its protein expression was decreased in later stages. The addition of collagen IV did not change the number of DDR1+/MBP+ cells but did accelerate OL branching. Here, we provide the first demonstration that collagen IV mediates the phosphorylation of DDR1 in HOG16 cells and that the in vitro co-expression of DDR1 and MBP is associated with accelerated branching during the differentiation of primary OLs.


Assuntos
Receptor com Domínio Discoidina 1 , Receptores Proteína Tirosina Quinases , Ratos , Humanos , Animais , Receptor com Domínio Discoidina 1/metabolismo , Ligantes , Colágeno Tipo IV/metabolismo , Oligodendroglia/metabolismo
2.
J Neuroinflammation ; 20(1): 7, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611185

RESUMO

BACKGROUND: Promotion of myelin repair in the context of demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also by impaired regeneration processes. Hence, this relates to replacement of lost oligodendrocytes and myelin sheaths-the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation and differentiation of resident oligodendroglial precursor cells (OPCs), whereas its efficiency remains limited and declines with disease progression and aging. Teriflunomide has been approved as a first-line treatment for relapsing remitting MS. Beyond its role in acting via inhibition of de novo pyrimidine synthesis leading to a cytostatic effect on proliferating lymphocyte subsets, this study aims to uncover its potential to foster myelin repair. METHODS: Within the cuprizone mediated de-/remyelination model teriflunomide dependent effects on oligodendroglial homeostasis and maturation, related to cellular processes important for myelin repair were analyzed in vivo. Teriflunomide administration was performed either as pulse or continuously and markers specific for oligodendroglial maturation and mitochondrial integrity were examined by means of gene expression and immunohistochemical analyses. In addition, axon myelination was determined using electron microscopy. RESULTS: Both pulse and constant teriflunomide treatment efficiently boosted myelin repair activities in this model, leading to accelerated generation of oligodendrocytes and restoration of myelin sheaths. Moreover, teriflunomide restored mitochondrial integrity within oligodendroglial cells. CONCLUSIONS: The link between de novo pyrimidine synthesis inhibition, oligodendroglial rescue, and maintenance of mitochondrial homeostasis appears as a key for successful myelin repair and hence for protection of axons from degeneration.


Assuntos
Bainha de Mielina , Oligodendroglia , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Crotonatos/farmacologia , Crotonatos/uso terapêutico , Hidroxibutiratos/metabolismo , Hidroxibutiratos/farmacologia , Diferenciação Celular
3.
Stroke ; 54(2): 575-586, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36490365

RESUMO

BACKGROUND: The migration of oligodendrocyte precursor cells (OPC) is a key process of remyelination, which is essential for the treatment of white matter stroke. This study aimed to investigate the role of HMGB1 (high mobility group box 1), a damage-associated molecular pattern released from dying oligodendrocytes, as an autocrine chemoattractant that promotes OPC migration. METHODS: The migratory capacity of primary cultured OPCs was measured using the Boyden chamber assay. The downstream pathway of HMGB1-mediated OPC migration was specified by siRNA-induced knockdown or pharmacological blockade of TLR2 (toll-like receptor 2), RAGE (receptor for advanced glycation end product), Src, ERK1/2 (extracellular signal-regulated kinase1/2), and FAK (focal adhesion kinase). Conditioned media were collected from oxygen-glucose deprivation-treated oligodendrocytes, and the impact on OPC migration was assessed. Lesion size and number of intralesional Olig2(+) cells were analyzed in an in vivo model of white matter stroke with N5-(1-iminoethyl)-L-ornithine (L-NIO). RESULTS: HMGB1 treatment promoted OPC migration. HMGB1 antagonism reversed such effects to untreated levels. Among the candidates for the downstream signal of HMGB1-mediated migration, the knockdown of TLR2 rather than that of RAGE attenuated the migration-promoting effect of HMGB1. Further specification of the HMGB1-TLR2 axis revealed that the phosphorylation of ERK1/2 and its downstream molecule FAK, rather than of Src, was decreased in TLR2-knockdown OPCs, and pharmacological inhibition of ERK1/2 and FAK led to decreased OPC migration. Oxygen-glucose deprivation-conditioned media promoted OPC migration, suggesting the autocrine chemoattractant function of HMGB1. In vivo, TLR2(-/-)-mice showed lesser intralesional Olig2(+) cells compared to wild-type controls in response to L-NIO induced ischemic injury regardless of HMGB1 administration. CONCLUSIONS: HMGB1, through the TLR2-ERK1/2-FAK axis, functions as an autocrine chemoattractant to promote OPC migration, which is an initial and indispensable step in remyelination. Thus, a novel treatment strategy for white matter stroke based on the HMGB1-TLR2 axis in the oligodendrocyte lineage could be feasible.


Assuntos
Proteína HMGB1 , Acidente Vascular Cerebral , Substância Branca , Camundongos , Animais , Receptor 2 Toll-Like/metabolismo , Substância Branca/patologia , Linhagem da Célula , Proteína HMGB1/metabolismo , Meios de Cultivo Condicionados/metabolismo , Oligodendroglia/metabolismo , Acidente Vascular Cerebral/patologia
4.
J Pharm Biomed Anal ; 224: 115196, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36529041

RESUMO

Recent studies show that shifts in energy metabolism in activated microglia are linked to their functions and immune responses in the ischemic brain. We previously reported that an antagonist of the bone morphogenetic protein, noggin, enhanced myelination in the ischemic brain during the chronic phase, and conditioned media (CM) from activated BV2 microglia treated with noggin after ischemia/reperfusion (I/R) increased the expression of myelin basic protein (MBP) in oligodendrocytes (MO3.13). To determine whether noggin induced changes in cell metabolism, metabolite profiles in BV2 and MO3.13 cells were analyzed by untargeted metabolomics using 1H nuclear magnetic resonance spectroscopy. Compared to vehicle-treated BV2 cells, noggin treatment (100 ng/mL for 3 h after I/R) suppressed the I/R-induced increase in intracellular glucose and lactate levels but increased extracellular levels of glucose and several amino acids. When MO3.13 cells were exposed to noggin CM from BV2 cells, most of the vehicle CM-induced changes in the levels of metabolites such as choline, formate, and intermediates of oxidative phosphorylation were reversed, while the glycerol level was markedly increased. An increase in glycerol level was also observed in the noggin-treated ischemic brain and was further supported by the expression of glycerol-3-phosphate dehydrogenase 1 (required for glycerol synthesis) in the cytoplasm of MBP-positive oligodendrocytes in the ischemic brains treated with noggin. These results suggest that noggin-induced changes in the metabolism of microglia provide a favorable environment for myelin synthesis in oligodendrocytes during the recovery phase after ischemic stroke.


Assuntos
Isquemia Encefálica , Humanos , Isquemia Encefálica/metabolismo , Glucose/metabolismo , Glicerol , Isquemia/metabolismo , Isquemia/patologia , Microglia , Oligodendroglia/metabolismo , Oligodendroglia/patologia
5.
Nature ; 613(7942): 120-129, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36517604

RESUMO

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFß1-TGFßR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.


Assuntos
Sistema Nervoso Central , Microglia , Bainha de Mielina , Adulto , Animais , Humanos , Camundongos , Axônios/metabolismo , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Microglia/citologia , Microglia/metabolismo , Microglia/patologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Cognição , Fator de Crescimento Transformador beta1/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Metabolismo dos Lipídeos , Envelhecimento/metabolismo , Envelhecimento/patologia
6.
J Comp Neurol ; 531(4): 515-527, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36477827

RESUMO

Oligodendrocytes are the myelinating cells in the central nervous system. In birds and mammals, the oligodendrocyte progenitor cells (OPCs) originate in the preoptic area (POA) of the hypothalamus. However, it remains unclear in other vertebrates such as fish. Thus, we have studied the early progression of OPCs during zebrafish visual morphogenesis from 2 days post fertilization (dpf) until 11 dpf using the olig2:EGFP transgenic line; and we have analyzed the differential expression of transcription factors involved in oligodendrocyte differentiation: Sox2 (using immunohistochemistry) and Sox10 (using the transgenic line sox10:tagRFP). The first OPCs (olig2:EGFP/Sox2) were found at 2 dpf in the POA. From 3 dpf onwards, these olig2:EGFP/Sox2 cells migrate to the optic chiasm, where they invade the optic nerve (ON), extending toward the retina. At 5 dpf, olig2:EGFP/Sox2 cells in the ON also colocalize with sox10:tagRFP. When olig2:EGFP cells differentiate and present more projections, they become positive only for sox10:tagRFP. olig2:EGFP/sox10: tagRFP cells ensheath the ON by 5 dpf when they also become positive for a myelin marker, based on the mbpa:tagRFPt transgenic line. We also found olig2:EGFP cells in other regions of the visual system. In the central retina at 2 dpf, they are positive for Sox2 but later become restricted to the proliferative germinal zone without this marker. In the ventricular areas of the optic tectum, olig2:EGFP cells present Sox2 but arborized ones sox10:tagRFP instead. Our data matches with other models, where OPCs are specified in the POA and migrate to the ON through the optic chiasm.


Assuntos
Oligodendroglia , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Diferenciação Celular/fisiologia , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Animais Geneticamente Modificados , Bainha de Mielina/fisiologia , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Mamíferos
7.
Biomolecules ; 12(12)2022 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-36551300

RESUMO

Neurodegeneration can benefit from ischemic preconditioning, a natural adaptive reaction to sublethal noxious stimuli. Although there is growing interest in advancing preconditioning to preserve brain function, preconditioning is not yet considered readily achievable in clinical settings. One of the most challenging issues is that there is no fine line between preconditioning stimuli and lethal stimuli. Here, we show deleterious effect of preconditioning on oligodendrocyte precursor cells (OPCs). We identified Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a mitochondrial BH3-only protein specifically involved in OPCs loss after preconditioning. Repeated ischemia stabilized BNIP3 and increased the vulnerability of OPCs to subsequent ischemic events. BNIP3 became mitochondrial-bound and was concurrent with the dysfunction of monocarboxylate transporter 1 (MCT1). Inhibition of BNIP3 by RNAi or necrostatin-1 (Nec-1) and knocking out of BNIP3 almost completely prevented OPCs loss and preserved white matter integrity. Together, our results suggest that the unfavorable effect of BNIP3 on OPCs should be noted for safe development of ischemic tolerance. BNIP3 inhibition appears to be a complementary approach to improve the efficacy of preconditioning for ischemic stroke.


Assuntos
Precondicionamento Isquêmico , Substância Branca , Oligodendroglia/metabolismo , Mitocôndrias/metabolismo
8.
Cell Death Dis ; 13(12): 1038, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36513635

RESUMO

Prenatal inflammatory insults accompany prematurity and provoke diffuse white matter injury (DWMI), which is associated with increased risk of neurodevelopmental pathologies, including autism spectrum disorders. DWMI results from maturation arrest of oligodendrocyte precursor cells (OPCs), a process that is poorly understood. Here, by using a validated mouse model of OPC maturation blockade, we provide the genome-wide ID card of the effects of neuroinflammation on OPCs that reveals the architecture of global cell fate issues underlining their maturation blockade. First, we find that, in OPCs, neuroinflammation takes advantage of a primed epigenomic landscape and induces abnormal overexpression of genes of the immune/inflammatory pathways: these genes strikingly exhibit accessible chromatin conformation in uninflamed OPCs, which correlates with their developmental, stage-dependent expression, along their normal maturation trajectory, as well as their abnormal upregulation upon neuroinflammation. Consistently, we observe the positioning on DNA of key transcription factors of the immune/inflammatory pathways (IRFs, NFkB), in both unstressed and inflamed OPCs. Second, we show that, in addition to the general perturbation of the myelination program, neuroinflammation counteracts the physiological downregulation of the cell cycle pathway in maturing OPCs. Neuroinflammation therefore perturbs cell identity in maturing OPCs, in a global manner. Moreover, based on our unraveling of the activity of genes of the immune/inflammatory pathways in prenatal uninflamed OPCs, the mere suppression of these proinflammatory mediators, as currently proposed in the field, may not be considered as a valid neurotherapeutic strategy.


Assuntos
Oligodendroglia , Substância Branca , Camundongos , Animais , Gravidez , Feminino , Oligodendroglia/metabolismo , Camundongos Transgênicos , Substância Branca/patologia , Epigenômica , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Diferenciação Celular , Ciclo Celular/genética , Epigênese Genética
9.
Nat Commun ; 13(1): 7791, 2022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36543778

RESUMO

The complexity of affected brain regions and cell types is a challenge for Huntington's disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identify PRKCE and Thiamine Pyrophosphokinase 1 (TPK1) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1 dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.


Assuntos
Biotina , Doença de Huntington , Oligodendroglia , Tiamina , Animais , Humanos , Camundongos , Biotina/metabolismo , Biotina/farmacologia , Suplementos Nutricionais , Modelos Animais de Doenças , Doença de Huntington/metabolismo , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/metabolismo , Núcleo Solitário/metabolismo , Tiamina/metabolismo , Tiamina/farmacologia
10.
Int J Mol Sci ; 23(24)2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36555377

RESUMO

Accumulating evidences suggest a strong correlation between metabolic changes and neurodegeneration in CNS demyelinating diseases such as multiple sclerosis (MS). Biotin, an essential cofactor for five carboxylases, is expressed by oligodendrocytes and involved in fatty acid synthesis and energy production. The metabolic effect of biotin or high-dose-biotin (MD1003) has been reported on rodent oligodendrocytes in vitro, and in neurodegenerative or demyelinating animal models. However, clinical studies, showed mild or no beneficial effect of MD1003 in amyotrophic lateral sclerosis (ALS) or MS. Here, we took advantage of a mouse model of myelin deficiency to study the effects of MD1003 on the behavior of murine and grafted human oligodendrocytes in vivo. We show that MD1003 increases the number and the differentiation potential of endogenous murine oligodendroglia over time. Moreover, the levels of MD1003 are increased in the plasma and brain of pups born to treated mothers, indicating that MD1003 can pass through the mother's milk. The histological analysis of the grafted animals shows that MD1003 increased proliferation and accelerates differentiation of human oligodendroglia, but without enhancing their myelination potential. These findings provide important insights into the role of MD1003 on murine and human oligodendrocyte maturation/myelination that may explain the mitigated outcome of ALS/MS clinical trials.


Assuntos
Esclerose Amiotrófica Lateral , Biotina , Esclerose Múltipla , Células Precursoras de Oligodendrócitos , Animais , Humanos , Camundongos , Esclerose Amiotrófica Lateral/metabolismo , Biotina/farmacologia , Diferenciação Celular , Esclerose Múltipla/metabolismo , Bainha de Mielina , Oligodendroglia/metabolismo
11.
Transl Psychiatry ; 12(1): 516, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36526621

RESUMO

Early-life adversity is associated with an increased risk of psychopathology, including mood disorders, later in life. Early-life stress affects several physiological systems, however, the exact mechanisms underlying pathological risk are not fully understood. This knowledge is crucial in developing appropriate therapeutic interventions. The prepubertal period is documented as a key developmental period for the maturation of the prefrontal cortex (PFC), a brain region involved in higher cognitive functions, including social function. In this study, we performed RNA sequencing on the PFC of adult rats who had experienced prepubertal stress (PPS) and controls to investigate the genome-wide consequences of this stress. PPS alters social behaviour in adulthood, therefore we also performed RNA sequencing on PPS and control rats following a social interaction test to determine social activity-dependent gene changes. At a baseline state (1 week following a social interaction test), no genes were differentially expressed in the PPS group. However, 1603 genes were differentially expressed in PPS rats compared to controls following a social interaction. These genes were enriched in biological pathways associated with cell signalling and axon myelination dynamics. Cell enrichment analysis showed these genes were associated with oligodendrocytes, and a comparison with an existing early-life stress sequencing dataset showed that pathways linked to oligodendrocyte morphology are impacted in a range of models of early-life stress in rodents. In conclusion, we identify pathways, including those involved in axon myelination, that are differentially activated in the adult in response to social stimulation following PPS. These differential responses may contribute to vulnerability to psychiatric pathology.


Assuntos
Interação Social , Estresse Psicológico , Animais , Ratos , Estresse Psicológico/metabolismo , Oligodendroglia/metabolismo , Córtex Pré-Frontal , Expressão Gênica
12.
Cell Rep ; 41(12): 111848, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36543124

RESUMO

Cerebral small vessel disease and brain white matter injury are worsened by cardiovascular risk factors including obesity. Molecular pathways in cerebral endothelial cells activated by chronic cerebrovascular risk factors alter cell-cell signaling, blocking endogenous and post-ischemic white matter repair. Using cell-specific translating ribosome affinity purification (RiboTag) in white matter endothelia and oligodendrocyte progenitor cells (OPCs), we identify a coordinated interleukin-chemokine signaling cascade within the oligovascular niche of subcortical white matter that is triggered by diet-induced obesity (DIO). DIO induces interleukin-17B (IL-17B) signaling that acts on the cerebral endothelia through IL-17Rb to increase both circulating and local endothelial expression of CXCL5. In white matter endothelia, CXCL5 promotes the association of OPCs with the vasculature and triggers OPC gene expression programs regulating cell migration through chemokine signaling. Targeted blockade of IL-17B reduced vessel-associated OPCs by reducing endothelial CXCL5 expression. In multiple human cohorts, blood levels of CXCL5 function as a diagnostic and prognostic biomarker of vascular cognitive impairment.


Assuntos
Lesões Encefálicas , Substância Branca , Camundongos , Humanos , Animais , Interleucina-17/metabolismo , Substância Branca/metabolismo , Células Endoteliais/metabolismo , Encéfalo/metabolismo , Transdução de Sinais , Lesões Encefálicas/metabolismo , Oligodendroglia/metabolismo , Quimiocina CXCL5/metabolismo
13.
Int J Mol Sci ; 23(23)2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36499195

RESUMO

Demyelinating disorders show impaired remyelination due to failure in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-forming oligodendrocytes, a process driven by microglia-OPC crosstalk. Through conducting a transcriptomic analysis of microarray studies on the demyelination-remyelination cuprizone model and using human samples of multiple sclerosis (MS), we identified molecules involved in this crosstalk. Differentially expressed genes (DEGs) of specific regions/cell types were detected in GEO transcriptomic raw data after cuprizone treatment and in MS samples, followed by functional analysis with GO terms and WikiPathways. Additionally, microglia-OPC crosstalk between microglia ligands, OPC receptors and target genes was examined with the NicheNet model. We identified 108 and 166 DEGs in the demyelinated corpus callosum (CC) at 2 and 4 weeks of cuprizone treatment; 427 and 355 DEGs in the remyelinated (4 weeks of cuprizone treatment + 14 days of normal diet) compared to 2- and 4-week demyelinated CC; 252 DEGs in MS samples and 2730 and 12 DEGs in OPC and microglia of 4-week demyelinated CC. At this time point, we found 95 common DEGs in the CC and OPCs, and one common DEG in microglia and OPCs, mostly associated with myelin and lipid metabolism. Crosstalk analysis identified 47 microglia ligands, 43 OPC receptors and 115 OPC target genes, all differentially expressed in cuprizone-treated samples and associated with myelination. Our differential expression pipeline identified demyelination/remyelination transcriptomic biomarkers in studies using diverse platforms and cell types/tissues. Cellular crosstalk analysis yielded novel markers of microglia ligands, OPC receptors and target genes.


Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Células Precursoras de Oligodendrócitos , Remielinização , Camundongos , Animais , Humanos , Células Precursoras de Oligodendrócitos/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Camundongos Endogâmicos C57BL , Remielinização/genética , Cuprizona/toxicidade , Oligodendroglia/metabolismo , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Diferenciação Celular/genética , Microglia/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Modelos Animais de Doenças
14.
Nature ; 611(7937): 769-779, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36385529

RESUMO

APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.


Assuntos
Apolipoproteína E4 , Encéfalo , Colesterol , Fibras Nervosas Mielinizadas , Oligodendroglia , Animais , Humanos , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Colesterol/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Autopsia , Células-Tronco Pluripotentes Induzidas , Neurônios/metabolismo , Neurônios/patologia , Heterozigoto , Transporte Biológico , Homeostase , Análise de Célula Única , Memória , Envelhecimento/genética , Perfilação da Expressão Gênica , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia
15.
Proc Natl Acad Sci U S A ; 119(48): e2202580119, 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36417438

RESUMO

Neurons in the developing brain undergo extensive structural refinement as nascent circuits adopt their mature form. This physical transformation of neurons is facilitated by the engulfment and degradation of axonal branches and synapses by surrounding glial cells, including microglia and astrocytes. However, the small size of phagocytic organelles and the complex, highly ramified morphology of glia have made it difficult to define the contribution of these and other glial cell types to this crucial process. Here, we used large-scale, serial section transmission electron microscopy (TEM) with computational volume segmentation to reconstruct the complete 3D morphologies of distinct glial types in the mouse visual cortex, providing unprecedented resolution of their morphology and composition. Unexpectedly, we discovered that the fine processes of oligodendrocyte precursor cells (OPCs), a population of abundant, highly dynamic glial progenitors, frequently surrounded small branches of axons. Numerous phagosomes and phagolysosomes (PLs) containing fragments of axons and vesicular structures were present inside their processes, suggesting that OPCs engage in axon pruning. Single-nucleus RNA sequencing from the developing mouse cortex revealed that OPCs express key phagocytic genes at this stage, as well as neuronal transcripts, consistent with active axon engulfment. Although microglia are thought to be responsible for the majority of synaptic pruning and structural refinement, PLs were ten times more abundant in OPCs than in microglia at this stage, and these structures were markedly less abundant in newly generated oligodendrocytes, suggesting that OPCs contribute substantially to the refinement of neuronal circuits during cortical development.


Assuntos
Neocórtex , Células Precursoras de Oligodendrócitos , Animais , Camundongos , Axônios/metabolismo , Oligodendroglia/metabolismo , Neurônios/metabolismo
16.
Nat Commun ; 13(1): 6813, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357389

RESUMO

Oligovascular coupling contributes to white matter vascular homeostasis. However, little is known about the effects of oligovascular interaction on oligodendrocyte precursor cell (OPC) changes in chronic cerebral ischemia. Here, using a mouse of bilateral carotid artery stenosis, we show a gradual accumulation of OPCs on vasculature with impaired oligodendrogenesis. Mechanistically, chronic ischemia induces a substantial loss of endothelial caveolin-1 (Cav-1), leading to vascular secretion of heat shock protein 90α (HSP90α). Endothelial-specific over-expression of Cav-1 or genetic knockdown of vascular HSP90α restores normal vascular-OPC interaction, promotes oligodendrogenesis and attenuates ischemic myelin damage. miR-3074(-1)-3p is identified as a direct inducer of Cav-1 reduction in mice and humans. Endothelial uptake of nanoparticle-antagomir improves myelin damage and cognitive deficits dependent on Cav-1. In summary, our findings demonstrate that vascular abnormality may compromise oligodendrogenesis and myelin regeneration through endothelial Cav-1, which may provide an intercellular mechanism in ischemic demyelination.


Assuntos
Isquemia Encefálica , MicroRNAs , Células Precursoras de Oligodendrócitos , Humanos , Caveolina 1/genética , Caveolina 1/metabolismo , Endotélio Vascular/metabolismo , Isquemia Encefálica/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Bainha de Mielina/metabolismo , Isquemia/metabolismo , Oligodendroglia/metabolismo , MicroRNAs/metabolismo
17.
Cells ; 11(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36359880

RESUMO

Myelin, critical for the correct function of the nervous system, is organized in different patterns that can include long non-myelinated axonal segments. How myelin patterning is regulated remains unexplained. The carbohydrate-binding protein galectin-4 (Gal-4) influences oligodendrocyte differentiation in vitro and is associated with non-myelinable axon segments (NMS) in cultured neurons. In consequence, Gal-4 has been proposed as a myelin patterning regulator, although no in vivo studies have corroborated this hypothesis. We used Gal-4-deficient mice (Lgals4-KO) to study the role of Gal-4 in cortical myelination in vivo. We show that cultured neurons of Lgals4-KO mice form NMS that are regulated as in control neurons. In addition, oligodendrocyte/myelin markers expression measured by biochemical and immunochemical means, and cortical myelin microstructure studied by in-depth image analysis appear unaltered in these animals. Consistently, myelin displays an essentially normal function assessed by in vivo electrophysiology and locomotion analyses. In conclusion, cortical myelin of Lgals4-KO mice does not show any significant defect in composition, organization or function, pointing to a negligible role of Gal-4 in myelination in vivo or, as discussed, to unknown mechanisms that compensate its absence.


Assuntos
Galectina 4 , Oligodendroglia , Animais , Camundongos , Galectina 4/metabolismo , Oligodendroglia/metabolismo , Bainha de Mielina/metabolismo , Axônios/metabolismo , Neurogênese
18.
Nucleic Acids Res ; 50(20): 11509-11528, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36318265

RESUMO

Differentiated oligodendrocytes produce myelin and thereby ensure rapid nerve impulse conduction and efficient information processing in the vertebrate central nervous system. The Krüppel-like transcription factor KLF9 enhances oligodendrocyte differentiation in culture, but appears dispensable in vivo. Its mode of action and role within the oligodendroglial gene regulatory network are unclear. Here we show that KLF9 shares its expression in differentiating oligodendrocytes with the closely related KLF13 protein. Both KLF9 and KLF13 bind to regulatory regions of genes that are important for oligodendrocyte differentiation and equally recognized by the central differentiation promoting transcription factors SOX10 and MYRF. KLF9 and KLF13 physically interact and synergistically activate oligodendrocyte-specific regulatory regions with SOX10 and MYRF. Similar to KLF9, KLF13 promotes differentiation and myelination in primary oligodendroglial cultures. Oligodendrocyte differentiation is also altered in KLF13-deficient mice as demonstrated by a transiently reduced myelin gene expression during the first postnatal week. Considering mouse phenotypes, the similarities in expression pattern and genomic binding and the behaviour in functional assays, KLF9 and KLF13 are important and largely redundant components of the gene regulatory network in charge of oligodendrocyte differentiation and myelination.


Assuntos
Bainha de Mielina , Fatores de Transcrição , Animais , Camundongos , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Oligodendroglia/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Expressão Gênica , Diferenciação Celular/genética , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo
19.
Mol Neurodegener ; 17(1): 77, 2022 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-36435784

RESUMO

The aberrant accumulation of α-Synuclein within oligodendrocytes is an enigmatic, pathological feature specific to Multiple system atrophy (MSA). Since the characterization of the disease in 1969, decades of research have focused on unravelling the pathogenic processes that lead to the formation of oligodendroglial cytoplasmic inclusions. The discovery of aggregated α-Synuclein (α-Syn) being the primary constituent of glial cytoplasmic inclusions has spurred several lines of research investigating the relationship between the pathogenic accumulation of the protein and oligodendrocytes. Recent developments have identified the ability of α-Syn to form conformationally distinct "strains" with varying behavioral characteristics and toxicities. Such "strains" are potentially disease-specific, providing insight into the enigmatic nature of MSA. This review discusses the evidence for MSA-specific α-Syn strains, highlighting the current methods for detecting and characterizing MSA patient-derived α-Syn. Given the differing behaviors of α-Syn strains, we explore the seeding and spreading capabilities of MSA-specific strains, postulating their influence on the aggressive nature of the disease. These ideas culminate into one key question: What causes MSA-specific strain formation? To answer this, we discuss the interplay between oligodendrocytes, neurons and α-Syn, exploring the ability of each cell type to contribute to the aggregate formation while postulating the effect of additional variables such as protein interactions, host characteristics and environmental factors. Thus, we propose the idea that MSA strain formation results from the intricate interrelation between neurons and oligodendrocytes, with deficits in each cell type required to initiate α-Syn aggregation and MSA pathogenesis.


Assuntos
Atrofia de Múltiplos Sistemas , Humanos , Atrofia de Múltiplos Sistemas/patologia , alfa-Sinucleína/metabolismo , Encéfalo/metabolismo , Oligodendroglia/metabolismo , Neurônios/metabolismo
20.
Int J Mol Sci ; 23(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36362204

RESUMO

Tamalin is a post-synaptic scaffolding protein that interacts with group 1 metabotropic glutamate receptors (mGluRs) and several other proteins involved in protein trafficking and cytoskeletal events, including neuronal growth and actin reorganization. It plays an important role in synaptic plasticity in vitro by controlling the ligand-dependent trafficking of group 1 mGluRs. Abnormal regulation of mGluRs in the central nervous system (CNS) is associated with glutamate-mediated neurodegenerative disorders. However, the pathological consequences of tamalin deficiency in the CNS are unclear. In this study, tamalin knockout (KO) zebrafish and mice exhibited neurodegeneration along with oligodendrocyte degeneration in the post-embryonic CNS to adulthood without any developmental defects, thus suggesting the function of tamalin is more important in the postnatal stage to adulthood than that in CNS development. Interestingly, hypomyelination was independent of axonal defects in the CNS of tamalin knockout zebrafish and mice. In addition, the loss of Arf6, a downstream signal of tamalin scaffolding protein, synergistically induced neurodegeneration in tamalin KO zebrafish even in the developing CNS. Furthermore, tamalin KO zebrafish displayed increased mGluR5 expression. Taken together, tamalin played an important role in neuronal and oligodendrocyte survival and myelination through the regulation of mGluR5 in the CNS.


Assuntos
Proteínas de Transporte , Peixe-Zebra , Animais , Camundongos , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , Sistema Nervoso Central/metabolismo
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