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1.
Neuron ; 51(1): 29-42, 2006 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-16815330

RESUMO

Degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive dysfunction in Alzheimer's disease (AD) and Down's syndrome (DS). We used Ts65Dn and Ts1Cje mouse models of DS to show that the increased dose of the amyloid precursor protein gene, App, acts to markedly decrease NGF retrograde transport and cause degeneration of BFCNs. NGF transport was also decreased in mice expressing wild-type human APP or a familial AD-linked mutant APP; while significant, the decreases were less marked and there was no evident degeneration of BFCNs. Because of evidence suggesting that the NGF transport defect was intra-axonal, we explored within cholinergic axons the status of early endosomes (EEs). NGF-containing EEs were enlarged in Ts65Dn mice and their App content was increased. Our study thus provides evidence for a pathogenic mechanism for DS in which increased expression of App, in the context of trisomy, causes abnormal transport of NGF and cholinergic neurodegeneration.


Assuntos
Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/metabolismo , Fibras Colinérgicas/patologia , Síndrome de Down/fisiopatologia , Degeneração Neural/metabolismo , Fator de Crescimento Neural/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/genética , Animais , Transporte Axonal/genética , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/patologia , Núcleo Basal de Meynert/fisiopatologia , Fibras Colinérgicas/metabolismo , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/metabolismo , Endossomos/genética , Endossomos/metabolismo , Endossomos/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/fisiopatologia , Fator de Crescimento Neural/genética , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Transporte Proteico/genética , Regulação para Cima/genética
2.
J Cell Biol ; 163(2): 223-9, 2003 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-14581450

RESUMO

Disruption of the BPAG1 (bullous pemphigoid antigen 1) gene results in progressive deterioration in motor function and devastating sensory neurodegeneration in the null mice. We have previously demonstrated that BPAG1n1 and BPAG1n3 play important roles in organizing cytoskeletal networks in vivo. Here, we characterize functions of a novel BPAG1 neuronal isoform, BPAG1n4. Results obtained from yeast two-hybrid screening, blot overlay binding assays, and coimmunoprecipitations demonstrate that BPAG1n4 interacts directly with dynactin p150Glued through its unique ezrin/radixin/moesin domain. Studies using double immunofluorescent microscopy and ultrastructural analysis reveal physiological colocalization of BPAG1n4 with dynactin/dynein. Disruption of the interaction between BPAG1n4 and dynactin results in severe defects in retrograde axonal transport. We conclude that BPAG1n4 plays an essential role in retrograde axonal transport in sensory neurons. These findings might advance our understanding of pathogenesis of axonal degeneration and neuronal death.


Assuntos
Autoantígenos/metabolismo , Transporte Axonal/genética , Axônios/metabolismo , Proteínas de Transporte , Colágeno/metabolismo , Proteínas do Citoesqueleto , Proteínas do Tecido Nervoso , Neurônios Aferentes/metabolismo , Colágenos não Fibrilares , Animais , Animais Recém-Nascidos , Autoantígenos/química , Autoantígenos/genética , Autoantígenos/ultraestrutura , Axônios/ultraestrutura , Células COS , Chlorocebus aethiops , Colágeno/química , Colágeno/genética , Colágeno/ultraestrutura , Complexo Dinactina , Dineínas/metabolismo , Dineínas/ultraestrutura , Distonina , Gânglios Espinais/metabolismo , Gânglios Espinais/ultraestrutura , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/ultraestrutura , Células NIH 3T3 , Neurônios Aferentes/ultraestrutura , Penfigoide Bolhoso/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/ultraestrutura , Estrutura Terciária de Proteína , Colágeno Tipo XVII
3.
Neuron ; 39(1): 69-84, 2003 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-12848933

RESUMO

Target-derived NGF promotes the phenotypic maintenance of mature dorsal root ganglion (DRG) nociceptive neurons. Here, we provide in vivo and in vitro evidence for the presence within DRG neurons of endosomes containing NGF, activated TrkA, and signaling proteins of the Rap1/Erk1/2, p38MAPK, and PI3K/Akt pathways. Signaling endosomes were shown to be retrogradely transported in the isolated sciatic nerve in vitro. NGF injection in the peripheral target of DRG neurons increased the retrograde transport of p-Erk1/2, p-p38, and pAkt in these membranes. Conversely, NGF antibody injections decreased the retrograde transport of p-Erk1/2 and p-p38. Our results are evidence that signaling endosomes, with the characteristics of early endosomes, convey NGF signals from the target of nociceptive neurons to their cell bodies.


Assuntos
Transporte Axonal/fisiologia , Endossomos/metabolismo , Fator de Crescimento Neural/fisiologia , Neurônios Aferentes/fisiologia , Transdução de Sinais/fisiologia , Animais , Células Cultivadas , Endossomos/ultraestrutura , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Gânglios Espinais/ultraestrutura , Imuno-Histoquímica , Microscopia Eletrônica , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios Aferentes/ultraestrutura , Técnicas de Cultura de Órgãos , Transporte Proteico/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor trkA/fisiologia , Nervo Isquiático/citologia , Nervo Isquiático/metabolismo
4.
J Clin Invest ; 111(4): 507-14, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12588889

RESUMO

Hedgehog proteins modulate development and patterning of the embryonic nervous system. As expression of desert hedgehog and the hedgehog receptor, patched-1, persist in the postnatal and adult peripheral nerves, the hedgehog pathway may have a role in maturation and maintenance of the peripheral nervous system in normal and disease states. We measured desert hedgehog expression in the peripheral nerve of maturing diabetic rats and found that diabetes caused a significant reduction in desert hedgehog mRNA. Treating diabetic rats with a sonic hedgehog-IgG fusion protein fully restored motor- and sensory-nerve conduction velocities and maintained the axonal caliber of large myelinated fibers. Diabetes-induced deficits in retrograde transport of nerve growth factor and sciatic-nerve levels of calcitonin gene-related product and neuropeptide Y were also ameliorated by treatment with the sonic hedgehog-IgG fusion protein, as was thermal hypoalgesia in the paw. These studies implicate disruption of normal hedgehog function in the etiology of diabetes-induced peripheral-nerve dysfunction and indicate that delivery of exogenous hedgehog proteins may have therapeutic potential for the treatment of diabetic neuropathy.


Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Transativadores/uso terapêutico , Animais , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/fisiopatologia , Proteínas Hedgehog , Humanos , Imunoglobulina G/genética , Imunoglobulina G/uso terapêutico , Masculino , Condução Nervosa/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia , Transativadores/genética
5.
Trends Neurosci ; 26(2): 73-80, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12536130

RESUMO

Advances in understanding the biology of neurotrophic factors and their signaling pathways have provided important insights into the normal growth, differentiation and maintenance of neurons. Stimulated by neuropathological observations and genetic discoveries, studies in cell and animal models of neurodegenerative disorders have begun to clarify pathogenetic mechanisms. We examine the intersection of these research themes and identify several potential mechanisms for linking failed neurotrophic factor signaling to neurodegeneration. Studies of nerve growth factor signaling in a mouse model of Down syndrome encourage the views that neuronal dysfunction and atrophy might be linked to failed neurotrophic support and that additional studies focused on this possibility would enhance our understanding of the mechanisms of neurodegenerative disorders and their treatment.


Assuntos
Doença de Alzheimer/metabolismo , Síndrome de Down/metabolismo , Fatores de Crescimento Neural/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos , Camundongos , Emaranhados Neurofibrilares/metabolismo , Placa Amiloide/metabolismo , Tauopatias/metabolismo , Proteínas tau/metabolismo
6.
Prog Brain Res ; 146: 3-23, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14699953

RESUMO

Nerve growth factor (NGF) activates TrkA to trigger signaling events that promote the survival, differentiation and maintenance of neurons. The mechanism(s) that controls the retrograde transport of the NGF signal from axon terminals to neuron cell bodies is not known. The 'signaling endosome' hypothesis stipulates that NGF, TrkA and signaling proteins are retrogradely transported on endocytic vesicles. Here, we provide evidence for the existence of signaling endosomes. Following NGF treatment, clathrin-coated vesicles (CCVs) contain NGF bound to TrkA together with activated signaling proteins of the Ras/pErk1/2 pathway. NGF signals from isolated CCVs through the Erk1/2 pathway. Early endosomes appear to represent a second type of signaling endosomes. We found that NGF induced a sustained activation of Rap1, a small monomeric GTP-binding protein of the Ras family, and that this activation occurred in early endosomes that contain key elements of Rap1/pErk1/2 pathway. We discuss the possibility that the failure of retrograde NGF signaling in a mouse model of Down syndrome (Ts65Dn) may be due to the failure to retrograde transport signaling endosomes. It is important to define further the significance of signaling endosomes in the biology of both normal and degenerating neurons.


Assuntos
Cadaverina/análogos & derivados , Degeneração Neural/metabolismo , Fator de Crescimento Neural/fisiologia , Neurônios/metabolismo , Transporte Proteico/fisiologia , Receptor trkA , Transdução de Sinais/fisiologia , Complexo 2 de Proteínas Adaptadoras/metabolismo , Animais , Western Blotting/métodos , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cadaverina/farmacologia , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Clorpromazina/farmacologia , Proteínas Cromossômicas não Histona/metabolismo , Vesículas Revestidas/efeitos dos fármacos , Vesículas Revestidas/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Antagonistas de Dopamina/farmacologia , Endossomos/metabolismo , Imunofluorescência/métodos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Fator de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Células PC12 , Fosfotirosina/metabolismo , Potássio/farmacologia , Testes de Precipitina/métodos , Ensaio Radioligante , Ratos , Fatores de Tempo , Proteínas de Transporte Vesicular , Proteínas rap1 de Ligação ao GTP/metabolismo
7.
Neurosci Lett ; 351(3): 181-5, 2003 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-14623136

RESUMO

The effect of peripheral axon crush on the axonal transport of the neurotrophin receptors, p75(NTR) and trkA, was studied in dorsal roots of adult rats. Lumbar dorsal roots were crushed for 3-6 h to cause accumulation of p75(NTR) and trkA. Immunohistochemistry showed the presence of the NGF receptors in axons, indicating retrograde and anterograde axonal transport in the dorsal root. Western blots confirmed that the time course of accumulation of p75(NTR) was consistent with fast axonal transport. However, trkA accumulation was too low to indicate significant levels of axonal transport. Sciatic nerve crush induced a 2-fold increase (P<0.05) in the bidirectional axonal transport of p75(NTR) in the dorsal root while trkA transport remained below detectable levels.


Assuntos
Transporte Axonal/fisiologia , Neurônios Aferentes/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Neuropatia Ciática/metabolismo , Animais , Masculino , Compressão Nervosa/métodos , Vias Neurais/metabolismo , Ratos , Ratos Wistar , Receptor de Fator de Crescimento Neural
8.
Front Neurosci ; 8: 20, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24574957

RESUMO

Hypothalamic orexin/hypocretin neurons send long axonal projections through the dorsal spinal cord in lamina I-II of the dorsal horn (DH) at the interface with the peripheral nervous system (PNS). We show that in the DH OXA fibers colocalize with substance P (SP) positive afferents of dorsal root ganglia (DRG) neurons known to mediate sensory processing. Further, OR1 is expressed in p75(NTR) and SP positive DRG neurons, suggesting a potential signaling pathway between orexin and DRG neurons. Interestingly, DRG sensory neurons have a distinctive bifurcating axon where one branch innervates the periphery and the other one the spinal cord (pseudo-unipolar neurons), allowing for potential functional coupling of distinct targets. We observe that OR1 is transported selectively from DRG toward the spinal cord, while OXA is accumulated retrogradely toward the DRG. We hence report a rare situation of asymmetrical neuropeptide receptor distribution between axons projected by a single neuron. These molecular and cellular data are consistent with the role of OXA/OR1 in sensory processing, including DRG neuronal modulation, and support the potential existence of an OX/HCRT circuit between CNS and PNS.

9.
Traffic ; 8(11): 1503-20, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17822405

RESUMO

Rap1 transduces nerve growth factor (NGF)/tyrosine receptor kinase A (TrkA) signaling in early endosomes, leading to sustained activation of the p44/p42 mitogen-activated protein kinases (MAPK1/2). However, the mechanisms by which NGF, TrkA and Rap1 are trafficked to early endosomes are poorly defined. We investigated trafficking and signaling of NGF, TrkA and Rap1 in PC12 cells and in cultured rat dorsal root ganglion (DRG) neurons. Herein, we show a role for both microtubule- and dynein-based transport in NGF signaling through MAPK1/2. NGF treatment resulted in trafficking of NGF, TrkA and Rap1 to early endosomes in the perinuclear region of PC12 cells where sustained activation of MAPK1/2 was observed. Disruption of microtubules with nocodazole in PC12 cells had no effect on the activation of TrkA and Ras. However, it disrupted intracellular trafficking of TrkA and Rap1. Moreover, NGF-induced activation of Rap1 and sustained activation of MAPK1/2 were markedly suppressed. Inhibition of dynein activity through overexpression of dynamitin (p50) blocked trafficking of Rap1 and the sustained phase of MAPK1/2 activation in PC12 cells. Remarkably, even in the continued presence of NGF, mature DRG neurons that overexpressed p50 became atrophic and most (>80%) developing DRG neurons died. Dynein- and microtubule-based transport is thus necessary for TrkA signaling to Rap1 and MAPK1/2.


Assuntos
Dineínas/química , Microtúbulos/metabolismo , Fator de Crescimento Neural/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo , Animais , Apoptose , Axônios/metabolismo , Complexo Dinactina , Gânglios Espinais/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/metabolismo , Células PC12 , Transporte Proteico , Ratos , Receptor trkA/metabolismo
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