Notch Signalling in the Hippocampus of Patients With Motor Neuron Disease

Gómez‐Pinedo, Ulises; Galán, Lucía; Matías‐Guiu, Jordi A.; Pytel, Vanesa; Moreno, Teresa de Santos; Guerrero-Solá, A.

doi:10.3389/fnins.2019.00302

Cited by 18 publications

(14 citation statements)

References 67 publications

(79 reference statements)

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“…Animal and human studies indicate TGFβ-system dysregulations and impaired neurogenesis as a common feature of neurodegenerative disorders, particularly in ALS, Alzheimer's disease, and Huntington's disease [14,[43][44][45][46][47]. A very recent review by Kandasamy et al describes the role of TGFβ in the context of vascular dementia and highlights the TGFβ-system as a therapeutic target to reinstall regenerative plasticity [48].…”

Section: (A) (B) (C)mentioning

confidence: 99%

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling

et al. 2021

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Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor—Receptor Type II) specific LNA-antisense oligonucleotide (“locked nucleotide acid”—“NVP-13”), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.

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Section: (A) (B) (C)mentioning

confidence: 99%

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling

et al. 2021

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“…Moreover, the Msi-1 protein was present in an oligomeric state in AD brains, forming aggregates 93 . In addition, Notch1 expression was significantly higher in the hippocampus of patients with amyotrophic lateral sclerosis (ALS), although the immunoreactivity of NICD was lower, suggesting that the Notch pathway is inactivated 94 . However, the Notch pathway was abnormally overactivated in the spinal cords of sporadic ALS and ALS model mice 95 , suggesting that aberrant Notch pathway activation contributes to ALS pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Potential roles of stem cell marker genes in axon regeneration

Lee

Cho

2021

Exp Mol Med

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Axon regeneration is orchestrated by many genes that are differentially expressed in response to injury. Through a comparative analysis of gene expression profiling, injury-responsive genes that are potential targets for understanding the mechanisms underlying regeneration have been revealed. As the efficiency of axon regeneration in both the peripheral and central nervous systems can be manipulated, we suggest that identifying regeneration-associated genes is a promising approach for developing therapeutic applications in vivo. Here, we review the possible roles of stem cell marker- or stemness-related genes in axon regeneration to gain a better understanding of the regeneration mechanism and to identify targets that can enhance regenerative capacity.

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“…Prior study also uncovered the role of the Notch signaling pathway in many neuron‐related diseases (Zhang et al, 2018). For example, inactivation of the Notch signaling pathway was reported to be a vital factor in decreased neurogenic response in the hippocampi of patients diagnosed with amyotrophic lateral sclerosis (Gómez‐Pinedo et al, 2019). Notch‐1 is one of the structurally similar Notch ligands, and has been found to interact with miRNAs in many neuron‐related diseases, such as Epileptiform (Wang, Zheng, et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

miR‐139‐5p upregulation alleviated spontaneous recurrent epileptiform discharge‐induced oxidative stress and apoptosis in rat hippocampal neurons via regulating the Notch pathway

Zhao

Yang

Wang

et al. 2020

Cell Biology International

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Epilepsy was characterized by the occurrence of spontaneous recurrent epileptiform discharges (SREDs) in neurons. Previous studies suggested that microRNA (miR)−139‐5p and the Notch pathway were implicated in epilepsy; however, their interaction remained vague. Rat primary hippocampal neurons were isolated and identified by immunofluorescence staining. The cells were then used for SREDs model construction and further subjected to flow cytometry for apoptosis detection. Contents of lactate dehydrogenase (LDH), malondialdehyde (MDA), super oxidase dismutase (SOD) contents, and reactive oxygen species (ROS), and the level of mitochondrial membrane potential (MMP) were determined using commercial kits. Target gene and potential binding sites of miR‐139‐5p were predicted with TargetScan and confirmed by dual‐luciferase reporter assay. Expressions of miR‐139‐5p, Notch pathway‐related proteins and apoptosis‐related proteins were measured by quantitative real‐time polymerase chain reaction and western blot as needed. The results showed that the hippocampal neurons were microtubule‐associated protein 2 (MAP2)‐positive. miR‐139‐5p was downregulated in SREDs model cells. SREDs promoted apoptosis and increased the contents of LDH, MDA, and ROS and the level of MMP while reducing miR‐139‐5p expression and SOD content in cells, which was reversed by miR‐139‐5p overexpression. Notch‐1 was recognized as the target gene of miR‐139‐5p, and its expression was negatively regulated by miR‐139‐5p. Besides, Notch‐1 overexpression reversed the effects of miR‐139‐5p upregulation on the expressions of Notch pathway‐related proteins and apoptosis‐related proteins, cell apoptosis, oxidative stress and MMP in SREDs‐treated cells. Our results indicated that miR‐139‐5p upregulation alleviated SREDs‐induced oxidative stress and cell apoptosis via regulating the Notch pathway, which provides new insights into the role of miRNA in the occurrence and development of epilepsy.

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Notch Signalling in the Hippocampus of Patients With Motor Neuron Disease

Cited by 18 publications

References 67 publications

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling

Potential roles of stem cell marker genes in axon regeneration

miR‐139‐5p upregulation alleviated spontaneous recurrent epileptiform discharge‐induced oxidative stress and apoptosis in rat hippocampal neurons via regulating the Notch pathway

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