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1.
Nat Commun ; 10(1): 5448, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784514

RESUMO

Amphisomes are organelles of the autophagy pathway that result from the fusion of autophagosomes with late endosomes. While biogenesis of autophagosomes and late endosomes occurs continuously at axon terminals, non-degradative roles of autophagy at boutons are barely described. Here, we show that in neurons BDNF/TrkB traffick in amphisomes that signal locally at presynaptic boutons during retrograde transport to the soma. This is orchestrated by the Rap GTPase-activating (RapGAP) protein SIPA1L2, which connects TrkB amphisomes to a dynein motor. The autophagosomal protein LC3 regulates RapGAP activity of SIPA1L2 and controls retrograde trafficking and local signaling of TrkB. Following induction of presynaptic plasticity, amphisomes dissociate from dynein at boutons enabling local signaling and promoting transmitter release. Accordingly, sipa1l2 knockout mice show impaired BDNF-dependent presynaptic plasticity. Taken together, the data suggest that in hippocampal neurons, TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.


Assuntos
Autofagossomos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Endossomos/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Plasticidade Neuronal/genética , Neurônios/metabolismo , Terminações Pré-Sinápticas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Transporte Axonal , Axônios/metabolismo , Dineínas/metabolismo , Proteínas Ativadoras de GTPase/genética , Hipocampo , Camundongos , Camundongos Knockout , Transporte Proteico
2.
PLoS Genet ; 12(3): e1005907, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26977770

RESUMO

Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Dendritos/metabolismo , Hipocampo/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hormônio Liberador de Gonadotropina/metabolismo , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Fosforilação , RNA Mensageiro/biossíntese , Transdução de Sinais , Sinapses/genética , Sinapses/metabolismo
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