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1.
EMBO J ; 37(17)2018 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-30049711

RESUMEN

Hippocampal GABAergic interneurons are crucial for cortical network function and have been implicated in psychiatric disorders. We show here that Neuregulin 3 (Nrg3), a relatively little investigated low-affinity ligand, is a functionally dominant interaction partner of ErbB4 in parvalbumin-positive (PV) interneurons. Nrg3 and ErbB4 are located pre- and postsynaptically, respectively, in excitatory synapses on PV interneurons in vivo Additionally, we show that ablation of Nrg3 results in a similar phenotype as the one described for ErbB4 ablation, including reduced excitatory synapse numbers on PV interneurons, altered short-term plasticity, and disinhibition of the hippocampal network. In culture, presynaptic Nrg3 increases excitatory synapse numbers on ErbB4+ interneurons and affects short-term plasticity. Nrg3 mutant neurons are poor donors of presynaptic terminals in the presence of competing neurons that produce recombinant Nrg3, and this bias requires postsynaptic ErbB4 but not ErbB4 kinase activity. Furthermore, when presented by non-neuronal cells, Nrg3 induces postsynaptic membrane specialization. Our data indicate that Nrg3 provides adhesive cues that facilitate excitatory neurons to synapse onto ErbB4+ interneurons.


Asunto(s)
Hipocampo/metabolismo , Interneuronas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Red Nerviosa/metabolismo , Plasticidad Neuronal , Sinapsis/metabolismo , Animales , Hipocampo/citología , Interneuronas/citología , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Transgénicos , Red Nerviosa/citología , Neurregulinas , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Sinapsis/genética
2.
Genes Dev ; 28(3): 290-303, 2014 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-24493648

RESUMEN

Myelination depends on the synthesis of large amounts of myelin transcripts and proteins and is controlled by Nrg1/ErbB/Shp2 signaling. We developed a novel pulse labeling strategy based on stable isotope labeling with amino acids in cell culture (SILAC) to measure the dynamics of myelin protein production in mice. We found that protein synthesis is dampened in the maturing postnatal peripheral nervous system, and myelination then slows down. Remarkably, sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination, resulting in continuous myelin growth. MAPK activation leads to minor changes in transcript levels but massively up-regulates protein production. Pharmacological interference in vivo demonstrates that the effects of activated MAPK signaling on translation are mediated by mTOR-independent mechanisms but in part also by mTOR-dependent mechanisms. Previous work demonstrated that loss of ErbB3/Shp2 signaling impairs Schwann cell development and disrupts the myelination program. We found that activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination.


Asunto(s)
Diferenciación Celular , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Vaina de Mielina/metabolismo , Neurregulina-1/metabolismo , Receptor ErbB-3/metabolismo , Células de Schwann/citología , Alelos , Animales , Regulación de la Expresión Génica/genética , MAP Quinasa Quinasa 1/genética , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Microscopía Electrónica de Transmisión , Complejos Multiproteicos , Mutación , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Receptor ErbB-3/genética , Células de Schwann/ultraestructura , Transducción de Señal , Serina-Treonina Quinasas TOR
3.
Front Med (Lausanne) ; 8: 744625, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34513895

RESUMEN

Since the implementation of the EU Orphan Regulation in 2000, the Committee for Orphan Medicinal Products at the European Medicines Agency has been evaluating the benefits of proposed orphan medicines vs. satisfactory treatment methods. This type of evaluation is foreseen in the Orphan Regulation as the orphan designation criterion called the "significant benefit." In this article, based on 20 years of experience, we provide a commentary explaining what is considered a satisfactory method of treatment in the context of the EU Orphan Regulation and for the purpose of the assessment of significant benefit. We discuss the challenges posed by continuously changing clinical practise, which is associated with the increasing number of treatment options, evolving nature of medicinal therapeutic indications and our understanding of them.

4.
Drug Discov Today ; 25(2): 274-291, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31704277

RESUMEN

This review provides an overview of nonclinical in vivo models that can be used to support orphan designation in selected rare infectious diseases in Europe, with the aim to inform and stimulate the planning of nonclinical development in this area of often neglected diseases.


Asunto(s)
Enfermedades Transmisibles/tratamiento farmacológico , Enfermedades Desatendidas/tratamiento farmacológico , Producción de Medicamentos sin Interés Comercial , Enfermedades Raras/tratamiento farmacológico , Animales , Humanos
5.
Drug Discov Today ; 23(1): 26-48, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28987289

RESUMEN

Here, we provide an in-depth literature and experience-based review of nonclinical models and data used to support orphan medicinal product designations (OMPDs) in rare neurodegenerative conditions. The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency updates its assessment processes based on scientific progress and aims to provide transparent criteria required in support of OMPDs. Thus, we also provide an updated analysis of existing nonclinical models in selected conditions and identify key features of nonclinical studies that are crucial for the support of OMPDs. This could not only inform future drug development in rare neurological conditions, but also indicate areas where the use of nonclinical models can be made more efficient.


Asunto(s)
Enfermedades del Sistema Nervioso , Producción de Medicamentos sin Interés Comercial , Enfermedades Raras , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos
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