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1.
J Neurosci ; 34(9): 3419-28, 2014 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-24573298

RESUMEN

The neurotrophin receptor p75(NTR) has been implicated in mediating neuronal apoptosis after injury to the CNS. Despite its frequent induction in pathologic states, there is limited understanding of the mechanisms that regulate p75(NTR) expression after injury. Here, we show that after focal cerebral ischemia in vivo or oxygen-glucose deprivation in organotypic hippocampal slices or neurons, p75(NTR) is rapidly induced. A concomitant induction of proNGF, a ligand for p75(NTR), is also observed. Induction of this ligand/receptor system is pathologically relevant, as a decrease in apoptosis, after oxygen-glucose deprivation, is observed in hippocampal neurons or slices after delivery of function-blocking antibodies to p75(NTR) or proNGF and in p75(NTR) and ngf haploinsufficient slices. Furthermore, a significant decrease in infarct volume was noted in p75(NTR)-/- mice compared with the wild type. We also investigated the regulatory mechanisms that lead to post-ischemic induction of p75(NTR). We demonstrate that induction of p75(NTR) after ischemic injury is independent of transcription but requires active translation. Basal levels of p75(NTR) in neurons are maintained in part by the expression of microRNA miR-592, and an inverse correlation is seen between miR-592 and p75(NTR) levels in the adult brain. After cerebral ischemia, miR-592 levels fall, with a corresponding increase in p75(NTR) levels. Importantly, overexpression of miR-592 in neurons decreases the level of ischemic injury-induced p75(NTR) and attenuates activation of pro-apoptotic signaling and cell death. These results identify miR-592 as a key regulator of p75(NTR) expression and point to a potential therapeutic candidate to limit neuronal apoptosis after ischemic injury.


Asunto(s)
Apoptosis/fisiología , Regulación de la Expresión Génica/fisiología , Infarto de la Arteria Cerebral Media/patología , MicroARNs/metabolismo , Neuronas/fisiología , Receptores de Factor de Crecimiento Nervioso/metabolismo , Factores de Edad , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Glucosa/deficiencia , Hipocampo/patología , Humanos , Hipoxia , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/genética , Factor de Crecimiento Nervioso/metabolismo , Precursores de Proteínas/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores de Factor de Crecimiento Nervioso/genética
2.
Nat Commun ; 14(1): 3956, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-37407548

RESUMEN

The ability to use blood to predict the outcomes of Parkinson's disease, including disease progression and cognitive and motor complications, would be of significant clinical value. We undertook bulk RNA sequencing from the caudate and putamen of postmortem Parkinson's disease (n = 35) and control (n = 40) striatum, and compared molecular profiles with clinical features and bulk RNA sequencing data obtained from antemortem peripheral blood. Cognitive and motor complications of Parkinson's disease were associated with molecular changes in the caudate (stress response) and putamen (endothelial pathways) respectively. Later and earlier-onset Parkinson's disease were molecularly distinct, and disease duration was associated with changes in caudate (oligodendrocyte development) and putamen (cellular senescence), respectively. Transcriptome patterns in the postmortem Parkinson's disease brain were also evident in antemortem peripheral blood, and correlated with clinical features of the disease. Together, these findings identify molecular signatures in Parkinson's disease patients' brain and blood of potential pathophysiologic and prognostic importance.


Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , Transcriptoma , Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Putamen
3.
J Biol Chem ; 286(34): 29556-67, 2011 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-21730062

RESUMEN

Brain-derived neurotrophic factor (BDNF) regulates neuronal differentiation, synaptic plasticity, and morphology, and modest changes in BDNF levels results in complex behavioral phenotypes. BDNF levels and intracellular localization in neurons are regulated by multiple mechanisms, including use of distinct promoters, mRNA and protein transport, and regulated cleavage of proBDNF to mature BDNF. Sortilin is an intracellular chaperone that binds to the prodomain of BDNF to traffic it to the regulated secretory pathway. However, sortilin binds to numerous ligands and plays a major role in mannose 6-phosphate receptor-independent transport of lysosomal hydrolases utilizing motifs in the intracellular domain that mediate trafficking from the Golgi and late endosomes. Sortilin is modified by ectodomain shedding, although the biological implications of this are not known. Here we demonstrate that ADAM10 is the preferred protease to cleave sortilin in the extracellular stalk region, to release the ligand binding sortilin ectodomain from the transmembrane and cytoplasmic domains. We identify sortilin shedding at the cell surface and in an intracellular compartment. Both sortilin and BDNF are trafficked to and degraded by the lysosome in neurons, and this is dependent upon the sortilin cytoplasmic tail. Indeed, expression of the sortilin ectodomain, which corresponds to the domain released after shedding, impairs lysosomal targeting and degradation of BDNF. These findings characterize the regulation of sortilin shedding and identify a novel mechanism by which sortilin ectodomain shedding acts as a regulatory switch for delivery of BDNF to the secretory pathway or to the lysosome, thus modulating the bioavailability of endogenous BDNF.


Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Aparato de Golgi/metabolismo , Lisosomas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteínas ADAM , Proteína ADAM10 , Proteínas Adaptadoras del Transporte Vesicular/genética , Secuencias de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Aparato de Golgi/genética , Células HEK293 , Humanos , Lisosomas/genética , Proteínas de la Membrana , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Estructura Terciaria de Proteína , Transporte de Proteínas/fisiología , Ratas
4.
Glia ; 59(5): 708-19, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21322057

RESUMEN

Fibroblast growth factor (FGF)-2 is known to have important pleiotropic effects in neuronal and glial cells during various physiological and pathological events. To investigate the role of endogenous FGF-2 in the differentiation of astrocytes, we studied the expression of glial fibrillary acidic protein (GFAP) in the hindbrain of the FGF-2 null mouse. GFAP was drastically decreased in a region-specific manner in the hindbrain of the adult and developing FGF-2 null mouse without an associated change in the expression of alternate markers for astrocytes. The deficit was evident in the astrocytes of pontine and medullary gray matter but not in the white matter. The astrocytes of the gray and white matter were seen to express FGF-2 and FGF receptors in a distinct pattern. The methylation of histone H3 at lysine 4 residue (H3K4me2) associated with the STAT (signal transducer and activator of transcription)-binding site of the GFAP promoter was significantly decreased in the gray matter of the FGF-2 null mouse, suggesting a role for FGF-2 in the epigenetic regulation of astrocyte differentiation in vivo. These observations underscore the importance of FGF-2 in astroglial differentiation in the hindbrain and the heterogeneity of astrocytes in their requirement for FGF-2 as a differentiation inducing signal.


Asunto(s)
Astrocitos/metabolismo , Diferenciación Celular/fisiología , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Rombencéfalo/metabolismo , Animales , Sitios de Unión/fisiología , Western Blotting , Inmunoprecipitación de Cromatina , Factor 2 de Crecimiento de Fibroblastos/genética , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Hibridación in Situ , Metilación , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo
5.
Neurosci Lett ; 446(2-3): 117-22, 2008 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-18822346

RESUMEN

Massive neuronal activation by glutamate can result in an excessive rise in cytoplasmic calcium, a process ultimately leading to neuronal death. We have investigated the role of the transient receptor potential channel 1 (TRPC1) in mediating glutamate-induced neuron death. We show that 2-APB (a blocker of store-operated Ca2+ entry) dramatically reduces glutamate-induced cell death in hippocampal organotypic slice cultures and that glutamate-induced toxicity is accompanied by an increase in TRPC1 expression. RNAi mediated knock-down ofTRPC1 in slice cultures prevented glutamate-induced cell death, indicating that TRPC1 plays a prominent role in calcium entry following exposure to glutamate. Thus, TRPC1 may represent a promising target for pharmacological interventions to prevent or reduce glutamate-induced neuronal damage.


Asunto(s)
Señalización del Calcio/fisiología , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Degeneración Nerviosa/metabolismo , Neurotoxinas/metabolismo , Canales Catiónicos TRPC/metabolismo , Animales , Animales Recién Nacidos , Atrofia/genética , Atrofia/metabolismo , Atrofia/fisiopatología , Compuestos de Boro/farmacología , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Ácido Glutámico/toxicidad , Hipocampo/patología , Hipocampo/fisiopatología , Ratones , Ratones Endogámicos C57BL , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/fisiopatología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Neurotoxinas/toxicidad , Técnicas de Cultivo de Órganos , Interferencia de ARN/fisiología , Canales Catiónicos TRPC/efectos de los fármacos , Canales Catiónicos TRPC/genética
6.
Artículo en Inglés | MEDLINE | ID: mdl-26682091

RESUMEN

BACKGROUND: Post-stroke movement disorders occur in up to 4% of stroke patients. The movements can be complex and difficult to classify, which presents challenges when attempting to understand the clinical phenomenology and provide appropriate treatment. CASE REPORT: We present a 64-year-old male with an unusual movement in the arm contralateral to his ischemic stroke. The primary feature of the movement was an involuntary elevation of the arm, occurring only when he was walking. DISCUSSION: The differential diagnosis includes dystonia, spontaneous arm levitation, synkinesis, and spasticity. We discuss each of these diagnostic possibilities in detail.

7.
J Mol Neurosci ; 52(3): 425-33, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24242951

RESUMEN

Transient receptor potential channel 1 (TRPC1; a cation channel activated by store depletion and/or through an intracellular messenger) is expressed in a variety of tissues, including the brain. To study the physiological function of TRPC1, we investigated the role of endogenously expressed TRPC1 in glutamate-induced cell death, using the murine hippocampal cell line HT22. Knocking down TRPC1 mRNA using TRPC1-shRNA or blocking of TRPC channels using 2-APB (≥200 µM) robustly attenuated glutamate-induced cell death after 24 h of incubation with 5 mM glutamate. Glutamate toxicity in HT22 cells seems to involve metabotropic glutamate receptor mGluR5 since MPEP (2-methyl-6-(phenylethynyl)-pyridine), an mGluR5 antagonist (≥100 µM), abrogated glutamate toxicity. Furthermore, a direct activation of mGluR5 by CHPG [(RS)-chloro-5-hydroxyphenylglycine; 100 µM or 300 µM] promoted HT22 cell death. TRPC1 knock-down markedly reduced CHPG-induced cell death. These observations suggest that glutamate-induced cell death in HT22 cells activates mGluR5 receptors, which significantly increases Ca(2+) influx through TRPC1 channels. TRPC1 knock-down prevented glutamate- and CHPG-induced cell death, suggesting that glutamate-induced toxicity in HT22 cells is mediated through TRPC1 channels and an mGluR5-dependent pathway. Together, this work provides evidence for a novel receptor activation pathway of TRPC1 in glutamate-induced toxicity.


Asunto(s)
Ácido Glutámico/toxicidad , Neuronas/metabolismo , Canales Catiónicos TRPC/metabolismo , Animales , Muerte Celular , Línea Celular , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Hipocampo/citología , Ratones , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fenilacetatos/farmacología , Piridinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor del Glutamato Metabotropico 5/agonistas , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Canales Catiónicos TRPC/genética
8.
PLoS One ; 9(1): e87406, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24498100

RESUMEN

Pericyte and vascular smooth muscle cell (SMC) recruitment to the developing vasculature is an important step in blood vessel maturation. Brain-derived neurotrophic factor (BDNF), expressed by endothelial cells, activates the receptor tyrosine kinase TrkB to stabilize the cardiac microvasculature in the perinatal period. However, the effects of the BDNF/TrkB signaling on pericytes/SMCs and the mechanisms downstream of TrkB that promote vessel maturation are unknown. To confirm the involvement of TrkB in vessel maturation, we evaluated TrkB deficient (trkb (-/-)) embryos and observed severe cardiac vascular abnormalities leading to lethality in late gestation to early prenatal life. Ultrastructural analysis demonstrates that trkb(-/-) embryos exhibit defects in endothelial cell integrity and perivascular edema. As TrkB is selectively expressed by pericytes and SMCs in the developing cardiac vasculature, we generated mice deficient in TrkB in these cells. Mice with TrkB deficiency in perivascular cells exhibit reduced pericyte/SMC coverage of the cardiac microvasculature, abnormal endothelial cell ultrastructure, and increased vascular permeability. To dissect biological actions and the signaling pathways downstream of TrkB in pericytes/SMCs, human umbilical SMCs were treated with BDNF. This induced membranous protrusions and cell migration, events dependent on myosin light chain phosphorylation. Moreover, inhibition of Rho GTPase and the Rho-associated protein kinase (ROCK) prevented membrane protrusion and myosin light chain phosphorylation in response to BDNF. These results suggest an important role for BDNF in regulating migration of TrkB-expressing pericytes/SMCs to promote cardiac blood vessel ensheathment and functional integrity during development.


Asunto(s)
Vasos Coronarios/enzimología , Miocardio/enzimología , Miocitos del Músculo Liso/enzimología , Pericitos/enzimología , Proteínas Quinasas/metabolismo , Transducción de Señal/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Permeabilidad Capilar/fisiología , Vasos Coronarios/citología , Vasos Coronarios/embriología , Cardiopatías Congénitas/embriología , Cardiopatías Congénitas/enzimología , Cardiopatías Congénitas/genética , Humanos , Glicoproteínas de Membrana , Ratones , Ratones Mutantes , Pericitos/citología , Proteínas Quinasas/genética , Proteínas Tirosina Quinasas , Receptor trkB , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo
9.
Nat Commun ; 4: 2490, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24048383

RESUMEN

A common single-nucleotide polymorphism (SNP) in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This SNP is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism, we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75(NTR) and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand, which modulates neuronal morphology.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Conos de Crecimiento/metabolismo , Hipocampo/metabolismo , Polimorfismo de Nucleótido Simple , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Embrión de Mamíferos , Escherichia coli/genética , Regulación del Desarrollo de la Expresión Génica , Conos de Crecimiento/patología , Células HEK293 , Hipocampo/crecimiento & desarrollo , Hipocampo/patología , Humanos , Espectroscopía de Resonancia Magnética , Memoria/fisiología , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis/genética , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores de Factor de Crecimiento Nervioso/genética , Receptores de Factor de Crecimiento Nervioso/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
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