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1.
Hum Mutat ; 33(2): 351-4, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22065524

RESUMEN

Autosomal recessive ataxias are heterogeneous group of disorders characterized by cerebellar atrophy and peripheral sensorimotor neuropathy. Molecular characterization of this group of disorders identified a number of genes contributing to these overlapping phenotypes. Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive form of ataxia caused by mutations in the SETX gene. We report on a consanguineous family with autosomal recessive inheritance and clinical characteristics of AOA2, and no mutations in the SETX gene. We mapped the AOA locus in this family to chromosome 17p12-p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis.


Asunto(s)
Apraxias/genética , Ataxia Telangiectasia/genética , Ataxia/genética , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Hipoalbuminemia/genética , Mutación Missense , Fosfatidilinositol 3-Quinasas/genética , Adolescente , Adulto , Animales , Apraxias/diagnóstico , Ataxia/diagnóstico , Ataxia Telangiectasia/diagnóstico , Encéfalo/patología , Ataxia Cerebelosa/congénito , Consanguinidad , ADN Helicasas , Femenino , Orden Génico , Ligamiento Genético , Homocigoto , Humanos , Hipoalbuminemia/diagnóstico , Imagen por Resonancia Magnética , Masculino , Ratones , Enzimas Multifuncionales , Linaje , Fenotipo , ARN Helicasas/genética , Relaciones entre Hermanos , Adulto Joven
2.
Glia ; 59(9): 1296-303, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21732425

RESUMEN

Trophic interactions between neurons and enwrapping glia, and between neurons and target cells, provide plasticity to the mammalian nervous system. Here, we review evidence that analogous cell interactions operate in the development of the nervous system of the fruit-fly Drosophila. Homologues of the canonical mammalian trophic factors also maintain neuronal and glial survival in Drosophila, adjusting cell populations to enable appropriate function, and revealing commonalities in nervous system development across the animals. There are also differences between neuron-glia interactions in flies and humans, not surprisingly, because we are only related to flies through a remote common ancestor. Nevertheless, the shared cellular and molecular mechanisms underlying developmental plasticity and enwrapping glial functions, strengthen the opportunity to use Drosophila to understand the brain, to model brain diseases and to understand the involvement of glial cells in nervous system regeneration.


Asunto(s)
Drosophila/fisiología , Neuroglía/fisiología , Neuronas/fisiología , Animales , Recuento de Células , Muerte Celular/fisiología , Drosophila/citología , Humanos , Factores de Crecimiento Nervioso/fisiología , Plasticidad Neuronal/fisiología , Procesos Estocásticos
3.
J Cell Biol ; 216(5): 1421-1438, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28373203

RESUMEN

Cell number plasticity is coupled to circuitry in the nervous system, adjusting cell mass to functional requirements. In mammals, this is achieved by neurotrophin (NT) ligands, which promote cell survival via their Trk and p75NTR receptors and cell death via p75NTR and Sortilin. Drosophila NTs (DNTs) bind Toll receptors instead to promote neuronal survival, but whether they can also regulate cell death is unknown. In this study, we show that DNTs and Tolls can switch from promoting cell survival to death in the central nervous system (CNS) via a three-tier mechanism. First, DNT cleavage patterns result in alternative signaling outcomes. Second, different Tolls can preferentially promote cell survival or death. Third, distinct adaptors downstream of Tolls can drive either apoptosis or cell survival. Toll-6 promotes cell survival via MyD88-NF-κB and cell death via Wek-Sarm-JNK. The distribution of adaptors changes in space and time and may segregate to distinct neural circuits. This novel mechanism for CNS cell plasticity may operate in wider contexts.


Asunto(s)
Factores de Crecimiento Nervioso/metabolismo , Receptores Toll-Like/metabolismo , Animales , Recuento de Células , Muerte Celular , Supervivencia Celular , Drosophila , Plasticidad Neuronal , Transducción de Señal
4.
Peptides ; 23(6): 1069-76, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12126733

RESUMEN

Intracerebroventricular (ICV) injection of Agouti related protein (AgRP), an endogenous melanocortin 3 and 4 receptor (MC3/4-R) antagonist, produces a prolonged increase in food intake. To clarify the roles of the MC3-R and MC4-R in AgRP-induced hyperphagia, the feeding effect of AgRP (83-132) was compared with that of the selective MC4-R antagonist, JKC-363 (cyclic [Mpr11, D-Nal14, Cys18, Asp22-NH2]-beta-MSH11-22). Single ICV administration of AgRP (83-132) increased food intake for 48 h whilst ICV JKC-363 increased food intake for 8h. An increase in body weight at 24 and 48 h was observed following AgRP (83-132) but not JKC-363 treatment. These data suggest that the sustained orexigenic action of AgRP (83-132) may not be through MC4-R antagonism.


Asunto(s)
Apetito/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Proteínas/farmacología , Receptores de Corticotropina/metabolismo , Proteína Relacionada con Agouti , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Conducta Alimentaria , Humanos , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Masculino , Péptidos/química , Péptidos Cíclicos/farmacología , Ratas , Ratas Wistar , Receptor de Melanocortina Tipo 3 , Receptor de Melanocortina Tipo 4 , Receptores de Corticotropina/antagonistas & inhibidores , Factores de Tiempo , beta-MSH/análogos & derivados , beta-MSH/farmacología
5.
Neuropharmacology ; 59(6): 375-9, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20685215

RESUMEN

Agomelatine, a novel melatonin analogue and anti-depressant that acts as an agonist on melatonin receptors 1 and 2 and as an antagonist at the 5HT2C receptor, was tested for its effects on cell proliferation in the dentate gyrus of the adult rat hippocampus under intact and flattened corticosterone rhythm conditions. Agomelatine stimulated mitosis rates in the intact male rat. Flattening the daily corticosterone rhythm by inserting a subcutaneous pellet of this steroid prevented the action of agomelatine. However, adding a daily injection of corticosterone at CT1200 to rats with implanted corticosterone pellets failed to restore agomelatine's efficacy on cell proliferation. The 5HT2C receptor antagonist SB242084 stimulated progenitor cell proliferation in the dentate gyrus, while a 5HT2C agonist (RO600175) had no effect on cell proliferation alone, but counteracted that of agomelatine. These results suggest that agomelatine, a new anti-depressant, can stimulate progenitor cell mitosis in the dentate gyrus. Its action requires an intact diurnal corticosterone rhythm. The action of agomelatine on neurogenesis is likely to reside in its antagonism of the 5HT2C receptor, and suggests a mechanism distinct from that of fluoxetine, another anti-depressant, which, as previous work shows, acts through the 5HT1A receptor, but whose action is also blocked by a flattened corticosterone rhythm.


Asunto(s)
Acetamidas/farmacología , Proliferación Celular/efectos de los fármacos , Corticosterona/metabolismo , Giro Dentado/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Análisis de Varianza , Animales , Ritmo Circadiano/efectos de los fármacos , Corticosterona/farmacología , Giro Dentado/metabolismo , Inmunohistoquímica , Masculino , Melatonina/agonistas , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2C/metabolismo
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