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1.
J Neurosci ; 32(28): 9613-25, 2012 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-22787047

RESUMO

Mint adaptor proteins bind to the membrane-bound amyloid precursor protein (APP) and affect the production of pathogenic amyloid-ß (Aß) peptides related to Alzheimer's disease (AD). Previous studies have shown that loss of each of the three Mint proteins delays the age-dependent production of amyloid plaques in transgenic mouse models of AD. However, the cellular and molecular mechanisms underlying Mints effect on amyloid production are unclear. Because Aß generation involves the internalization of membrane-bound APP via endosomes and Mints bind directly to the endocytic motif of APP, we proposed that Mints are involved in APP intracellular trafficking, which in turn, affects Aß generation. Here, we show that APP endocytosis was attenuated in Mint knock-out neurons, revealing a role for Mints in APP trafficking. We also show that the endocytic APP sorting processes are regulated by Src-mediated phosphorylation of Mint2 and that internalized APP is differentially sorted between autophagic and recycling trafficking pathways. A Mint2 phosphomimetic mutant favored endocytosis of APP along the autophagic sorting pathway leading to increased intracellular Aß accumulation. Conversely, the Mint2 phospho-resistant mutant increased APP localization to the recycling pathway and back to the cell surface thereby enhancing Aß42 secretion. These results demonstrate that Src-mediated phosphorylation of Mint2 regulates the APP endocytic sorting pathway, providing a mechanism for regulating Aß secretion.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas de Transporte/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Fragmentos de Peptídeos/metabolismo , Quinases da Família src/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Biotinilação/métodos , Proteínas de Transporte/genética , Células Cultivadas , Córtex Cerebral/patologia , Chlorocebus aethiops , Modelos Animais de Doenças , Endocitose/genética , Endocitose/fisiologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/genética , Humanos , Camundongos , Camundongos Transgênicos , Mutação/genética , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fosforilação/genética , Presenilina-1/genética , Transporte Proteico/genética , Transfecção , Quinases da Família src/genética
2.
Artigo em Inglês | MEDLINE | ID: mdl-38083393

RESUMO

Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular progressive multisystem disease that results in a broad spectrum of clinical central nervous system (CNS) involvement, including problems with memory, attention, executive functioning, and social cognition. Fractional anisotropy and mean diffusivity along-tract data calculated using diffusion tensor imaging techniques play a vital role in assessing white matter microstructural changes associated with neurodegeneration caused by DM1. In this work, a novel spectrogram-based deep learning method is proposed to characterize white matter network alterations in DM1 with the goal of building a deep learning model as neuroimaging biomarkers of DM1. The proposed method is evaluated on fractional anisotropies and mean diffusivities along-tract data calculated for 25 major white matter tracts of 46 DM1 patients and 96 unaffected controls. The evaluation data consists of a total of 7100 spectrogram images. The model achieved 91% accuracy in identifying DM1, a significant improvement compared to previous methods.Clinical relevance- Clinical care of DM1 is particularly challenging due to DM1 multisystem involvement and the disease variability. Patients with DM1 often experience neurological and psychological symptoms, such as excessive sleepiness and apathy, that greatly impact their quality of life. Some of DM1 CNS symptoms may be responsive to treatment. The goal of this research is to gain a deeper understanding of the impact of DM1 on the CNS and to develop a deep learning model that can serve as a biomarker for the disease, with the potential to be used in future clinical trials as an outcome measure.


Assuntos
Distrofia Miotônica , Substância Branca , Humanos , Substância Branca/diagnóstico por imagem , Distrofia Miotônica/diagnóstico por imagem , Distrofia Miotônica/complicações , Distrofia Miotônica/psicologia , Imagem de Tensor de Difusão , Anisotropia , Qualidade de Vida , Neuroimagem
3.
Mol Cell Neurosci ; 45(1): 75-83, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20550966

RESUMO

Shal K(+) (K(v)4) channels in mammalian neurons have been shown to be localized exclusively to somato-dendritic regions of neurons, where they function as key determinants of dendritic excitability. To gain insight into the mechanisms underlying dendritic localization of K(v)4 channels, we use Drosophila melanogaster as our model system. We show that Shal K(+) channels display a conserved somato-dendritic localization in vivo in Drosophila. From a yeast-2-hybrid screen, we identify the novel interactor, SIDL (for Shal Interactor of Di-Leucine Motif), as the first target protein reported to bind the highly conserved di-leucine motif (LL-motif) implicated in dendritic targeting. We show that SIDL is expressed primarily in the nervous system, co-localizes with GFP-Shal channels in neurons, and interacts specifically with the LL-motif of Drosophila and mouse Shal channels. We disrupt the Shal-SIDL interaction by mutating the LL-motif on Shal channels, and show that Shal K(+) channels are then mislocalized to some, but not all, axons in vivo. These results suggest that there are multiple mechanisms underlying Shal K(+) channel targeting, one of which depends on the LL-motif. The identification of SIDL may provide the first step for future investigation into the molecular machinery regulating the LL-motif-dependent targeting of K(+) channels.


Assuntos
Dendritos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Canais de Potássio Shal/metabolismo , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/embriologia , Humanos , Camundongos , Neurônios/citologia , Neurônios/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Canais de Potássio Shal/genética , Técnicas do Sistema de Duplo-Híbrido
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