Neurotrophin‐3 restores synaptic plasticity in the striatum of a mouse model of Huntington's disease

Gómez‐Pineda, Victor G.; Torres‐Cruz, Francisco M.; Vivar‐Cortés, César I.; Hernández‐Echeagaray, Elizabeth

doi:10.1111/cns.12824

Cited by 22 publications

(12 citation statements)

References 42 publications

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“…Nevertheless, several studies have highlighted a dynamic regulation of NET by intracellular and extracellular molecules [18,35,36]. NET expression is regulated by growth factors, such as NT-3, transforming growth factor β1 (TGF-β1), and fibroblast growth factor-2 (FGF-2) [37,38]. Norepinephrine (NE) is transported into neurons by NET, a Na + /Cl − dependent neurotransmitter transporter whose blockade increases extracellular levels of NE (Figure 5) [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…In turn, NET exerts a dynamic control of extracellular NE concentration through reuptake of the NE released in the synaptic cleft, playing an important role in pre/postsynaptic homeostasis [18,47]. Evidence suggests that NT-3 regulates NET expression, for example, in cultured quail neural crest cells [38]. Thus, NT-3 modulates the synaptic transmission of NE and increases NE reuptake [48].…”

Section: Discussionmentioning

confidence: 99%

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The Role of the Second Extracellular Loop of Norepinephrine Transporter, Neurotrophin-3 and Tropomyosin Receptor Kinase C in T Cells: A Peripheral Biomarker in the Etiology of Schizophrenia

Rodrigues-Amorím

Iglesias-Martínez-Almeida

Rivera-Baltanás

et al. 2021

IJMS

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The neurobiology of schizophrenia is multifactorial, comprising the dysregulation of several biochemical pathways and molecules. This research proposes a peripheral biomarker for schizophrenia that involves the second extracellular loop of norepinephrine transporter (NEText), the tropomyosin receptor kinase C (TrkC), and the neurotrophin-3 (NT-3) in T cells. The study of NEText, NT-3, and TrkC was performed in T cells and plasma extracted from peripheral blood of 54 patients with schizophrenia and 54 healthy controls. Levels of NT-3, TrkC, and NET were significantly lower in plasma and T cells of patients compared to healthy controls. Co-immunoprecipitation (co-IPs) showed protein interactions with Co-IP NEText–NT-3 and Co-IP NEText–TrkC. Computational modelling of protein–peptide docking by CABS-dock provided a medium–high accuracy model for NT-3–NEText (4.6935 Å) and TrkC–NEText (2.1365 Å). In summary, immunocomplexes reached statistical relevance in the T cells of the control group contrary to the results obtained with schizophrenia. The reduced expression of NT-3, TrkC, and NET, and the lack of molecular complexes in T cells of patients with schizophrenia may lead to a peripheral dysregulation of intracellular signaling pathways and an abnormal reuptake of norepinephrine (NE) by NET. This peripheral molecular biomarker underlying schizophrenia reinforces the role of neurotrophins, and noradrenergic and immune systems in the pathophysiology of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Role of the Second Extracellular Loop of Norepinephrine Transporter, Neurotrophin-3 and Tropomyosin Receptor Kinase C in T Cells: A Peripheral Biomarker in the Etiology of Schizophrenia

Rodrigues-Amorím

Iglesias-Martínez-Almeida

Rivera-Baltanás

et al. 2021

IJMS

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“…Neurotrophin-3 ( Ntf3 ), a neurotrophic factor, showed increased expression after the 3rd MPTP/p injections. Ntf3 could restore synaptic plasticity in the striatum of a mouse model of Huntington’s disease [ 33 ]. Ntf3 could activate two membrane receptors: the low-affinity receptor p75 and the high-affinity receptor “tropomyosin receptor kinase” ( Trk ).…”

Section: Discussionmentioning

confidence: 99%

Molecular Regulatory Mechanism and Toxicology of Neurodegenerative Processes in MPTP/Probenecid-Induced Progressive Parkinson’s Disease Mice Model Revealed by Transcriptome

et al. 2020

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Parkinson’s disease (PD) is a neurodegenerative disease caused by a variety of unclear complex pathogenic factors. The 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced progressive PD mice is a well-recognized classic model for studying PD, but the molecular toxicology of this model is still unclear. Here, for the first time, we report gradual neurodegenerative processes in MPTP/p-induced progressive PD mice model using RNA-seq. Transcriptional responses are orchestrated to regulate the expression of many genes in substantia nigra, such as Ntf3, Pitx3, Th, and Drd2, leading to the degeneration of dopaminergic neurons at last. We proposed that the established model could be divided into three phases based on their molecular toxicological features: “the stress response phase” which maintained the microenvironment homeostasis, “the pre-neurodegenerative phase” which demonstrated observed MPTP/p cytotoxicity and gradual degeneration of dopaminergic neurons, and “the neurodegenerative phase” which reflected distinct damage and dopaminergic neuron apoptotic process. Glia cells exhibited a certain protective effect on dopaminergic neurons in 3rd and 6th MPTP/p-induced cytotoxicity. But in 10th MPTP/p injection, glia cells play a promoting role in PD and tissue damages caused by oxidative stress. This study also indicated that the substantia nigra of PD mice showed unique patterns of changes at each stage. Moreover, neurotrophic signaling pathway, ECM-receptor interaction, oxidative phosphorylation, apoptosis and necroptosis were enriched at 3rd and 6th MPTP/p injection, which might be associated with the PD progress. This study provided an extensive data set of molecular toxicology for elucidating of PD progression and offered comprehensive theoretical knowledge for the development of new therapy.

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“…Neurotrophin-3 is another trophic factor widely expressed in the nervous system, which acts by activation of the p75 receptor and of Trk C, B, and A receptors [ 268 ], and whose levels are reduced in HD [ 269 ]. It has been shown to reduce cellular damage, regulate neuronal plasticity and synapse formation, and promote neuronal regeneration [ 270 ], effects which all make neurotrophin-3 an appealing therapeutic target.…”

Section: Mechanisms Of Neurodegeneration In Huntington’s Diseasementioning

confidence: 99%

Molecular Pathophysiological Mechanisms in Huntington’s Disease

Jurcău

2022

Biomedicines

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Huntington’s disease is an inherited neurodegenerative disease described 150 years ago by George Huntington. The genetic defect was identified in 1993 to be an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 4. In the following almost 30 years, a considerable amount of research, using mainly animal models or in vitro experiments, has tried to unravel the complex molecular cascades through which the transcription of the mutant protein leads to neuronal loss, especially in the medium spiny neurons of the striatum, and identified excitotoxicity, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, altered axonal trafficking and reduced availability of trophic factors to be crucial contributors. This review discusses the pathogenic cascades described in the literature through which mutant huntingtin leads to neuronal demise. However, due to the ubiquitous presence of huntingtin, astrocytes are also dysfunctional, and neuroinflammation may additionally contribute to Huntington’s disease pathology. The quest for therapies to delay the onset and reduce the rate of Huntington’s disease progression is ongoing, but is based on findings from basic research.

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Neurotrophin‐3 restores synaptic plasticity in the striatum of a mouse model of Huntington's disease

Abstract: NT-3 modulates corticostriatal transmission through TrkB stimulation and restores striatal LTD by signaling through its TrkC receptor.

Cited by 22 publications

References 42 publications

The Role of the Second Extracellular Loop of Norepinephrine Transporter, Neurotrophin-3 and Tropomyosin Receptor Kinase C in T Cells: A Peripheral Biomarker in the Etiology of Schizophrenia

The Role of the Second Extracellular Loop of Norepinephrine Transporter, Neurotrophin-3 and Tropomyosin Receptor Kinase C in T Cells: A Peripheral Biomarker in the Etiology of Schizophrenia

Molecular Regulatory Mechanism and Toxicology of Neurodegenerative Processes in MPTP/Probenecid-Induced Progressive Parkinson’s Disease Mice Model Revealed by Transcriptome

Molecular Pathophysiological Mechanisms in Huntington’s Disease

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