RESUMEN
Neurons rely heavily on high mitochondrial metabolism to provide sufficient energy for proper development. However, it remains unclear how neurons maintain high oxidative phosphorylation (OXPHOS) during development. Mitophagy plays a pivotal role in maintaining mitochondrial quality and quantity. We herein describe that G protein-coupled receptor 50 (GPR50) is a novel mitophagy receptor, which harbors the LC3-interacting region (LIR) and is required in mitophagy under stress conditions. Although it does not localize in mitochondria under normal culturing conditions, GPR50 is recruited to the depolarized mitochondrial membrane upon mitophagy stress, which marks the mitochondrial portion and recruits the assembling autophagosomes, eventually facilitating the mitochondrial fragments to be engulfed by the autophagosomes. Mutations Δ502-505 and T532A attenuate GPR50-mediated mitophagy by disrupting the binding of GPR50 to LC3 and the mitochondrial recruitment of GPR50. Deficiency of GPR50 causes the accumulation of damaged mitochondria and disrupts OXPHOS, resulting in insufficient ATP production and excessive ROS generation, eventually impairing neuronal development. GPR50-deficient mice exhibit impaired social recognition, which is rescued by prenatal treatment with mitoQ, a mitochondrially antioxidant. The present study identifies GPR50 as a novel mitophagy receptor that is required to maintain mitochondrial OXPHOS in developing neurons.
Asunto(s)
Mitocondrias , Mitofagia , Neuronas , Receptores Acoplados a Proteínas G , Animales , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Neuronas/metabolismo , Mitocondrias/metabolismo , Ratones , Humanos , Fosforilación Oxidativa , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Especies Reactivas de Oxígeno/metabolismo , Ratones Noqueados , NeurogénesisRESUMEN
Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic Gi protein-coupled A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial reaction, ameliorating blood-brain barrier disruption, peripheral immune cell infiltration, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as an important pathway driving SAE and highlight the potential of targeting A1ARs for therapeutic intervention.
Asunto(s)
Adenosina , Astrocitos , Lipopolisacáridos , Ratones Endogámicos C57BL , Microglía , Receptor de Adenosina A1 , Encefalopatía Asociada a la Sepsis , Animales , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/inmunología , Adenosina/metabolismo , Ratones , Encefalopatía Asociada a la Sepsis/metabolismo , Receptor de Adenosina A1/metabolismo , Masculino , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Sepsis/inmunología , Sepsis/complicaciones , Enfermedades Neuroinflamatorias/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/inmunología , Encéfalo/efectos de los fármacos , Ratones Noqueados , Inflamación , Transducción de Señal/efectos de los fármacosRESUMEN
Oligodendrocyte precursor cells (OPCs) have long been regarded as progenitors of oligodendrocytes, yet recent advances have illuminated their multifaceted nature including their emerging immune functions. This review seeks to shed light on the immune functions exhibited by OPCs, spanning from phagocytosis to immune modulation and direct engagement with immune cells across various pathological scenarios. Comprehensive understanding of the immune functions of OPCs alongside their other roles will pave the way for targeted therapies in neurological disorders.
Asunto(s)
Células Precursoras de Oligodendrocitos , Humanos , Células Precursoras de Oligodendrocitos/inmunología , Animales , Fagocitosis/inmunología , Oligodendroglía/inmunología , Diferenciación Celular/inmunología , InmunomodulaciónRESUMEN
In the central nervous system, oligodendrocyte precursor cells (OPCs) are recognized as the progenitors responsible for the generation of oligodendrocytes, which play a critical role in myelination. Extensive research has shed light on the mechanisms underlying OPC proliferation and differentiation into mature myelin-forming oligodendrocytes. However, recent advances in the field have revealed that OPCs have multiple functions beyond their role as progenitors, exerting control over neural circuits and brain function through distinct pathways. This review aims to provide a comprehensive understanding of OPCs by first introducing their well-established features. Subsequently, we delve into the emerging roles of OPCs in modulating brain function in both healthy and diseased states. Unraveling the cellular and molecular mechanisms by which OPCs influence brain function holds great promise for identifying novel therapeutic targets for central nervous system diseases.
Asunto(s)
Células Precursoras de Oligodendrocitos , Células Precursoras de Oligodendrocitos/metabolismo , Vaina de Mielina/metabolismo , Encéfalo/metabolismo , Oligodendroglía/metabolismo , Sistema Nervioso Central , Diferenciación Celular/fisiologíaRESUMEN
Acute brain injuries evoke various response cascades directing the formation of the glial scar. Here, we report that acute lesions associated with hemorrhagic injuries trigger a re-programming of oligodendrocytes. Single-cell RNA sequencing highlighted a subpopulation of oligodendrocytes activating astroglial genes after acute brain injuries. By using PLP-DsRed1/GFAP-EGFP and PLP-EGFPmem/GFAP-mRFP1 transgenic mice, we visualized this population of oligodendrocytes that we termed AO cells based on their concomitant activity of astro- and oligodendroglial genes. By fate mapping using PLP- and GFAP-split Cre complementation and repeated chronic in vivo imaging with two-photon laser-scanning microscopy, we observed the conversion of oligodendrocytes into astrocytes via the AO cell stage. Such conversion was promoted by local injection of IL-6 and was diminished by IL-6 receptor-neutralizing antibody as well as by inhibiting microglial activation with minocycline. In summary, our findings highlight the plastic potential of oligodendrocytes in acute brain trauma due to microglia-derived IL-6.
Asunto(s)
Astrocitos , Lesiones Encefálicas , Ratones , Animales , Interleucina-6 , Proteína Ácida Fibrilar de la Glía/genética , Oligodendroglía , Ratones TransgénicosRESUMEN
Oligodendrocyte precursor cells (OPCs) are uniformly distributed in the mammalian brain; however, their function is rather heterogeneous in respect to their origin, location, receptor/channel expression and age. The basic helix-loop-helix transcription factor Olig2 is expressed in all OPCs as a pivotal determinant of their differentiation. Here, we identified a subset (2%-26%) of OPCs lacking Olig2 in various brain regions including cortex, corpus callosum, CA1 and dentate gyrus. These Olig2 negative (Olig2neg ) OPCs were enriched in the juvenile brain and decreased subsequently with age, being rarely detectable in the adult brain. However, the loss of this population was not due to apoptosis or microglia-dependent phagocytosis. Unlike Olig2pos OPCs, these subset cells were rarely labeled for the mitotic marker Ki67. And, accordingly, BrdU was incorporated only by a three-day long-term labeling but not by a 2-hour short pulse, suggesting these cells do not proliferate any more but were derived from proliferating OPCs. The Olig2neg OPCs exhibited a less complex morphology than Olig2pos ones. Olig2neg OPCs preferentially remain in a precursor stage rather than differentiating into highly branched oligodendrocytes. Changing the adjacent brain environment, for example, by acute injuries or by complex motor learning tasks, stimulated the transition of Olig2pos OPCs to Olig2neg cells in the adult. Taken together, our results demonstrate that OPCs transiently suppress Olig2 upon changes of the brain activity.
Asunto(s)
Lesiones Encefálicas , Células Precursoras de Oligodendrocitos , Animales , Células Precursoras de Oligodendrocitos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Factor de Transcripción 2 de los Oligodendrocitos/metabolismo , Oligodendroglía/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular , Lesiones Encefálicas/metabolismo , Mamíferos/metabolismoRESUMEN
The chaperon protein sigma-1 receptor (S1R) has been discovered over 40 years ago. Recent pharmacological studies using S1R exogenous ligands demonstrated a promising therapeutical potential of targeting the S1R in several neurological disorders. Although intensive in vitro studies have revealed S1Rs are mainly residing at the membrane of the endoplasmic reticulum (ER), the cell-specific in vivo expression pattern of S1Rs is still unclear, mainly because of the lack of a reliable detection method which also prevented a comprehensive functional analysis. Here, first, we identified a highly specific antibody using S1R knockout (KO) mice and established an immunohistochemical protocol involving a 1% sodium dodecyl sulphate (SDS) antigen retrieval step. Second, we characterized the S1R expression in the mouse brain and can demonstrate that the S1R is widely expressed: in principal neurons, interneurons and all glial cell types. In addition, unlike reported in previous studies, we showed that the S1R expression in astrocytes is not colocalized with the astrocytic cytoskeleton protein GFAP. Thus, our results raise concerns over previously reported S1R properties. Finally, we generated a Cre-dependent S1R conditional KO mouse (S1R flox) to study cell-type-specific functions of the S1R. As a proof of concept, we successfully ablated S1R expressions in neurons or microglia employing neuronal and microglial Cre-expressing mice, respectively. In summary, we provide powerful tools to cell-specifically detect, delete and functionally characterize S1R in vivo.
Asunto(s)
Neuronas , Receptores sigma , Ratones , Animales , Neuronas/metabolismo , Neuroglía/metabolismo , Receptores sigma/genética , Astrocitos/metabolismo , Ratones Noqueados , Receptor Sigma-1RESUMEN
Cortical neural circuits are complex but very precise networks of balanced excitation and inhibition. Yet, the molecular and cellular mechanisms that form the balance are just beginning to emerge. Here, using conditional γ-aminobutyric acid receptor B1- deficient mice we identify a γ-aminobutyric acid/tumor necrosis factor superfamily member 12-mediated bidirectional communication pathway between parvalbumin-positive fast spiking interneurons and oligodendrocyte precursor cells that determines the density and function of interneurons in the developing medial prefrontal cortex. Interruption of the GABAergic signaling to oligodendrocyte precursor cells results in reduced myelination and hypoactivity of interneurons, strong changes of cortical network activities and impaired social cognitive behavior. In conclusion, glial transmitter receptors are pivotal elements in finetuning distinct brain functions.
Asunto(s)
Células Precursoras de Oligodendrocitos , Animales , Cognición , Comunicación , Interneuronas/fisiología , Ratones , Células Precursoras de Oligodendrocitos/metabolismo , Parvalbúminas/metabolismoRESUMEN
Human brain organoids cultured from human pluripotent stem cells provide a promising platform to recapitulate histological features of the human brain and model neural disorders. However, unlike animal models, brain organoids lack a reproducible topographic organization, which limits their application in modeling intricate biology, such as the interaction between different brain regions. To overcome these drawbacks, brain organoids have been pre-patterned into specific brain regions and fused to form an assembloid that represents reproducible models recapitulating more complex biological processes of human brain development and neurological diseases. This approach has been applied to model interneuron migration, neuronal projections, tumor invasion, oligodendrogenesis, forebrain axis establishment, and brain vascularization. In this review article, we will summarize the usage of this technology to understand the fundamental biology underpinning human brain development and disorders.
RESUMEN
Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors. Deficiency of TRIM32 results in an impaired generation of GABAergic interneurons and autism-like behaviors in mice, concomitant with an elevated autophagy, which can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32-/- mice, indicating a causal contribution of GABAergic disinhibition. Thus, the present study suggests a novel mechanism for ASD etiology in that TRIM32 deficiency-caused hypoactive mTOR, which is linked to an elevated autophagy, leads to autism-like behaviors via impairing generation of GABAergic interneurons. TRIM32-/- mouse is a novel autism model mouse.
Asunto(s)
Trastorno Autístico/genética , Proliferación Celular/genética , Neuronas GABAérgicas/metabolismo , Interneuronas/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis/genética , Serina-Treonina Quinasas TOR/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Trastorno Autístico/metabolismo , Autofagia/efectos de los fármacos , Autofagia/genética , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Clonazepam/farmacología , Agonistas de Receptores de GABA-A/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Interneuronas/efectos de los fármacos , Ratones , Ratones Noqueados , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas RGS/metabolismoRESUMEN
Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Accumulated damaged mitochondria, which are associated with impaired mitophagy, contribute to neurodegeneration in AD. We show levels of Disrupted-in-schizophrenia-1 (DISC1), which is genetically associated with psychiatric disorders and AD, decrease in the brains of AD patients and transgenic model mice and in Aß-treated cultured cells. Disrupted-in-schizophrenia-1 contains a canonical LC3-interacting region (LIR) motif (210 FSFI213 ), through which DISC1 directly binds to LC3-I/II. Overexpression of DISC1 enhances mitophagy through its binding to LC3, whereas knocking-down of DISC1 blocks Aß-induced mitophagy. We further observe overexpression of DISC1, but not its mutant (muFSFI) which abolishes the interaction of DISC1 with LC3, rescues Aß-induced mitochondrial dysfunction, loss of spines, suppressed long-term potentiation (LTP). Overexpression of DISC1 via adeno-associated virus (serotype 8, AAV8) in the hippocampus of 8-month-old APP/PS1 transgenic mice for 4 months rescues cognitive deficits, synaptic loss, and Aß plaque accumulation, in a way dependent on the interaction of DISC1 with LC3. These results indicate that DISC1 is a novel mitophagy receptor, which protects synaptic plasticity from Aß accumulation-induced toxicity through promoting mitophagy.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Mitofagia , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal , Enfermedad de Alzheimer/complicaciones , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Autofagosomas/efectos de los fármacos , Autofagosomas/metabolismo , Autofagosomas/ultraestructura , Encéfalo/metabolismo , Encéfalo/patología , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Células HeLa , Humanos , Masculino , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Mitofagia/efectos de los fármacos , Modelos Biológicos , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Plasticidad Neuronal/efectos de los fármacos , Unión Proteica/efectos de los fármacosRESUMEN
Sphingolipids emerge as essential modulators in the etiology of Alzheimer's disease (AD) with unclear mechanisms. Elevated levels of SM synthase 1 (SMS1), which catalyzes the synthesis of SM from ceramide and phosphatidylcholine, have been observed in the brains of Alzheimer's disease (AD), where expression of ß-site APP cleaving enzyme 1 (BACE1), a rate limiting enzyme in amyloid-ß (Aß) generation, are upregulated. In the present study, we show knockdown of SMS1 via andeno associated virus (serotype 8, AAV8) in the hippocampus of APP/PS1 transgenic mice, attenuates the densities of Aß plaques, neuroinflammation, synaptic loss and thus rescuing cognitive deficits of these transgenic mice. We further describe that knockdown or inhibition of SMS1 decreases BACE1 stability, which is accompanied with decreased BACE1 levels in the Golgi, whereas enhanced BACE1 levels in the early endosomes and the lysosomes. The reduction of BACE1 levels induced by knockdown or inhibition of SMS1 is prevented by inhibition of lysosomes. Therefore, knockdown or inhibition of SMS1 promotes lysosomal degradation of BACE1 via modulating the intracellular trafficking of BACE1. Knockdown of SMS1 attenuates AD-like pathology through promoting lysosomal degradation of BACE1.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide , Ácido Aspártico Endopeptidasas/metabolismo , Lisosomas/metabolismo , Presenilina-1 , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismo , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Ácido Aspártico Endopeptidasas/genética , Técnicas de Silenciamiento del Gen/métodos , Células HEK293 , Humanos , Lisosomas/genética , Ratones , Ratones Transgénicos , Presenilina-1/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/antagonistas & inhibidores , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genéticaRESUMEN
Owing to its biocompatibility, noncytotoxicity, biodegradability and three-dimensional structure, vertically silicon nanowires (SiNWs) arrays are a promising scaffold material for tissue engineering, regenerative medicine and relevant medical applications. Recently, its osteogenic differentiation effects, reorganization of cytoskeleton and regulation of the fate on stem cells have been demonstrated. However, it still remains unknown whether SiNWs arrays could affect the proliferation and neuronal differentiation of neural stem cells (NSCs) or not. In the present study, we have employed vertically aligned SiNWs arrays as culture systems for NSCs and proved that the scaffold material could promote the proliferation and neuronal differentiation of NSCs while maintaining excellent cell viability and stemness. Immunofluorescence imaging analysis, Western blot and RT-PCR results reveal that NSCs proliferation and neuronal differentiation efficiency on SiNWs arrays are significant greater than that on silicon wafers. These results implicate SiNWs arrays could offer a powerful platform for NSCs research and NSCs-based therapy in the field of neural tissue engineering.