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1.
Sensors (Basel) ; 22(24)2022 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-36560254

RESUMEN

In this study, a noncontact fabric loop sensor based on magnetic-field-induced conductivity, which can simultaneously detect cardiac activity and respiration signals, was developed and the effects of the sensor's shape and measurement position on the sensing performance were analyzed. Fifteen male subjects in their twenties wore sleeveless shirts equipped with various types of fabric loop sensors (spiky, extrusion, and spiral), and the cardiac activity and respiratory signals were measured twice at positions P2, P4, and P6. The measurements were verified by comparing them against the reference electrocardiogram (ECG) and respiratory signals measured using BIOPAC® (MP150, ECG100B, RSP100C). The waveforms of the raw signal measured by the fabric loop sensor were filtered with a bandpass filter (1-20 Hz) and qualitatively compared with the ECG signal obtained from the Ag/AgCI electrode. Notwithstanding a slight difference in performance, the three fabric sensors could simultaneously detect cardiac activity and respiration signals at all measurement positions. In addition, it was verified through statistical analysis that the highest-quality signal was obtained at the measurement position of P4 or P6 using the spiral loop sensor.


Asunto(s)
Textiles , Dispositivos Electrónicos Vestibles , Humanos , Masculino , Respiración , Electrodos , Conductividad Eléctrica
2.
Sensors (Basel) ; 20(1)2020 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-31947865

RESUMEN

The purpose of this study was to investigate the effects of the shape and attachment position of stretchable textile piezoresistive sensors coated with single-walled carbon nanotubes on their performance in measuring the joint movements of children. The requirements for fabric motion sensors suitable for children are also identified. The child subjects were instructed to wear integrated clothing with sensors of different shapes (rectangular and boat-shaped), attachment positions (at the knee and elbow joints or 4 cm below the joints). The change in voltage caused by the elongation and contraction of the fabric sensors was measured for the flexion-extension motions of the arms and legs at 60°/s (three measurements of 10 repetitions each for the 60° and 90° angles, for a total of 60 repetitions). Their reliability was verified by analyzing the agreement between the fabric motion sensors and attached acceleration sensors. The experimental results showed that the fabric motion sensor that can measure children's arm and leg motions most effectively is the rectangular-shaped sensor attached 4 cm below the joint. In this study, we developed a textile piezoresistive sensor suitable for measuring the joint motion of children, and analyzed the shape and attachment position of the sensor on clothing suitable for motion sensing. We showed that it is possible to sense joint motions of the human body by using flexible fabric sensors integrated into clothing.


Asunto(s)
Articulaciones/fisiología , Monitoreo Fisiológico , Movimiento/fisiología , Textiles , Brazo/fisiología , Niño , Grafito/química , Humanos , Masculino , Nanotubos de Carbono/química
3.
Ann Neurol ; 77(6): 953-71, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25707991

RESUMEN

OBJECTIVE: Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. METHODS: The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. RESULTS: AZD0530 potently inhibits Fyn and prevents both Aßo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. INTERPRETATION: Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Benzodioxoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-fyn/antagonistas & inhibidores , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Benzodioxoles/farmacocinética , Modelos Animales de Enfermedad , Quinasa 2 de Adhesión Focal/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/farmacocinética
4.
J Sci Food Agric ; 96(7): 2433-9, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26243037

RESUMEN

BACKGROUND: Although rice (Oryza sativa L.) is the third largest food crop, relatively fewer studies have been reported on rice geographical origin based on light element isotope ratios in comparison with other foods such as wine, beef, juice, oil and milk. Therefore this study tries to discriminate the geographical origin of the same rice cultivars grown in different Asian countries using the analysis of C, N, O and S stable isotope ratios and chemometrics. RESULTS: The δ(15) NAIR , δ(18) OVSMOW and δ(34) SVCDT values of brown rice were more markedly influenced by geographical origin than was the δ(13) CVPDB value. In particular, the combination of δ(18) OVSMOW and δ(34) SVCDT more efficiently discriminated rice geographical origin than did the remaining combinations. Principal component analysis (PCA) revealed a clear discrimination between different rice geographical origins but not between rice genotypes. In particular, the first components of PCA discriminated rice cultivated in the Philippines from rice cultivated in China and Korea. CONCLUSION: The present findings suggest that analysis of the light element isotope composition combined with chemometrics can be potentially applicable to discriminate rice geographical origin and also may provide a valuable insight into the control of improper or fraudulent labeling regarding the geographical origin of rice worldwide. © 2015 Society of Chemical Industry.


Asunto(s)
Carbono/química , Nitrógeno/química , Oryza/química , Oxígeno/química , Azufre/química , Isótopos de Carbono , China , Isótopos de Nitrógeno , Isótopos de Oxígeno , Filipinas , República de Corea , Isótopos de Azufre
5.
EMBO J ; 30(1): 165-80, 2011 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-21119615

RESUMEN

Diacylglycerol (DAG) is an important lipid second messenger. DAG signalling is terminated by conversion of DAG to phosphatidic acid (PA) by diacylglycerol kinases (DGKs). The neuronal synapse is a major site of DAG production and action; however, how DGKs are targeted to subcellular sites of DAG generation is largely unknown. We report here that postsynaptic density (PSD)-95 family proteins interact with and promote synaptic localization of DGKι. In addition, we establish that DGKι acts presynaptically, a function that contrasts with the known postsynaptic function of DGKζ, a close relative of DGKι. Deficiency of DGKι in mice does not affect dendritic spines, but leads to a small increase in presynaptic release probability. In addition, DGKι-/- synapses show a reduction in metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) at neonatal (∼2 weeks) stages that involve suppression of a decrease in presynaptic release probability. Inhibition of protein kinase C normalizes presynaptic release probability and mGluR-LTD at DGKι-/- synapses. These results suggest that DGKι requires PSD-95 family proteins for synaptic localization and regulates presynaptic DAG signalling and neurotransmitter release during mGluR-LTD.


Asunto(s)
Encéfalo/metabolismo , Diacilglicerol Quinasa/análisis , Diacilglicerol Quinasa/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Sinapsis/metabolismo , Animales , Encéfalo/ultraestructura , Línea Celular , Células Cultivadas , Diacilglicerol Quinasa/genética , Maleato de Dizocilpina/metabolismo , Eliminación de Gen , Expresión Génica , Humanos , Ratones , Neuronas/metabolismo , Neuronas/ultraestructura , Neurotransmisores/metabolismo , Proteína Quinasa C/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica
6.
EMBO J ; 28(8): 1170-9, 2009 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-19229292

RESUMEN

Diacylglycerol (DAG) is an important lipid signalling molecule that exerts an effect on various effector proteins including protein kinase C. A main mechanism for DAG removal is to convert it to phosphatidic acid (PA) by DAG kinases (DGKs). However, it is not well understood how DGKs are targeted to specific subcellular sites and tightly regulates DAG levels. The neuronal synapse is a prominent site of DAG production. Here, we show that DGKzeta is targeted to excitatory synapses through its direct interaction with the postsynaptic PDZ scaffold PSD-95. Overexpression of DGKzeta in cultured neurons increases the number of dendritic spines, which receive the majority of excitatory synaptic inputs, in a manner requiring its catalytic activity and PSD-95 binding. Conversely, DGKzeta knockdown reduces spine density. Mice deficient in DGKzeta expression show reduced spine density and excitatory synaptic transmission. Time-lapse imaging indicates that DGKzeta is required for spine maintenance but not formation. We propose that PSD-95 targets DGKzeta to synaptic DAG-producing receptors to tightly couple synaptic DAG production to its conversion to PA for the maintenance of spine density.


Asunto(s)
Espinas Dendríticas/metabolismo , Diacilglicerol Quinasa/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Isoenzimas/metabolismo , Proteínas de la Membrana/metabolismo , Sinapsis/metabolismo , Transmisión Sináptica/fisiología , Animales , Células Cultivadas , Espinas Dendríticas/ultraestructura , Diacilglicerol Quinasa/genética , Diglicéridos/metabolismo , Homólogo 4 de la Proteína Discs Large , Guanilato-Quinasas , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Isoenzimas/genética , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Neuronas/citología , Neuronas/metabolismo , Técnicas de Placa-Clamp , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Ratas , Ratas Sprague-Dawley , Sinapsis/ultraestructura
7.
Prog Neurobiol ; 203: 102075, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34004220

RESUMEN

Amyloid-ß (Aß) and tau are major pathological hallmarks of Alzheimer's disease (AD). Several studies have revealed that Aß accelerates pathological tau transition and spreading during the disease progression, and that reducing tau can mitigate pathological features of AD. However, molecular links between Aß and tau pathologies remain elusive. Here, we suggest a novel role for the plexin-A4 as an Aß receptor that induces aggregated tau pathology. Plexin-A4, previously known as proteins involved in regulating axon guidance and synaptic plasticity, can bound to Aß with co-receptor, neuropilin-2. Genetic downregulation of plexin-A4 in neurons was sufficient to prevent Aß-induced activation of CDK5 and reduce tau hyperphosphorylation and aggregation, even in the presence of Aß. In an AD mouse model that manifests both Aß and tau pathologies, genetic downregulation of plexin-A4 in the hippocampus reduced tau pathology and ameliorated spatial memory impairment. Collectively, these results indicate that the plexin-A4 is capable of mediating Aß-induced tau pathology in AD pathogenesis.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide , Animales , Moléculas de Adhesión Celular , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso , Proteínas tau
8.
Prog Neurobiol ; 204: 102086, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34052305

RESUMEN

Successful clinical translation of stem cell-based therapy largely relies on the scalable and reproducible preparation of donor cells with potent therapeutic capacities. In this study, midbrain organoids were yielded from human pluripotent stem cells (hPSCs) to prepare cells for Parkinson's disease (PD) therapy. Neural stem/precursor cells (NSCs) isolated from midbrain organoids (Og-NSCs) expanded stably and differentiated into midbrain-type dopamine(mDA) neurons, and an unprecedentedly high proportion expressed midbrain-specific factors, with relatively low cell line and batch-to-batch variations. Single cell transcriptome analysis followed by in vitro assays indicated that the majority of cells in the Og-NSC cultures are ventral midbrain (VM)-patterned with low levels of cellular senescence/aging and mitochondrial stress, compared to those derived from 2D-culture environments. Notably, in contrast to current methods yielding mDA neurons without astrocyte differentiation, mDA neurons that differentiated from Og-NSCs were interspersed with astrocytes as in the physiologic brain environment. Thus, the Og-NSC-derived mDA neurons exhibited improved synaptic maturity, functionality, resistance to toxic insults, and faithful expressions of the midbrain-specific factors, in vitro and in vivo long after transplantation. Consequently, Og-NSC transplantation yielded potent therapeutic outcomes that are reproducible in PD model animals. Collectively, our observations demonstrate that the organoid-based method may satisfy the demands needed in the clinical setting of PD cell therapy.


Asunto(s)
Células-Madre Neurales , Enfermedad de Parkinson , Animales , Diferenciación Celular , Neuronas Dopaminérgicas , Humanos , Mesencéfalo , Organoides , Enfermedad de Parkinson/terapia
9.
J Neurosci ; 29(5): 1586-95, 2009 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-19193906

RESUMEN

IRSp53 is an adaptor protein that acts downstream of Rac and Cdc42 small GTPases and is implicated in the regulation of membrane deformation and actin filament assembly. In neurons, IRSp53 is an abundant postsynaptic protein and regulates actin-rich dendritic spines; however, its in vivo functions have not been explored. We characterized transgenic mice deficient of IRSp53 expression. Unexpectedly, IRSp53(-/-) neurons do not show significant changes in the density and ultrastructural morphologies of dendritic spines. Instead, IRSp53(-/-) neurons exhibit reduced AMPA/NMDA ratio of excitatory synaptic transmission and a selective increase in NMDA but not AMPA receptor-mediated transmission. IRSp53(-/-) hippocampal slices show a markedly enhanced long-term potentiation (LTP) with no changes in long-term depression. LTP-inducing theta burst stimulation enhances NMDA receptor-mediated transmission. Spatial learning and novel object recognition are impaired in IRSp53(-/-) mice. These results suggest that IRSp53 is involved in the regulation of NMDA receptor-mediated excitatory synaptic transmission, LTP, and learning and memory behaviors.


Asunto(s)
Potenciación a Largo Plazo/fisiología , Trastornos de la Memoria/metabolismo , Memoria/fisiología , Proteínas del Tejido Nervioso/deficiencia , Receptores de N-Metil-D-Aspartato/fisiología , Transmisión Sináptica/fisiología , Animales , Aprendizaje/fisiología , Masculino , Trastornos de la Memoria/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Ratas
10.
J Neurochem ; 112(3): 577-87, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19922438

RESUMEN

Diacylglycerol (DAG) is an important lipid-signaling molecule that binds and activates various downstream effectors. Tight control over the production and removal of DAG is important in maintaining the dynamic responses of the DAG signaling system to a changing environment. Diacylglycerol kinases (DGKs) are enzymes that convert DAG to phosphatidic acid (PA). This conversion terminates DAG signaling and, at the same time, initiates additional signaling events downstream of PA, which also acts as a lipid-signaling molecule. However, little is known about how (or if) DGKs are targeted to specific subcellular sites or how DGKs tightly regulate local DAG and PA signaling. Dendritic spines are tiny protrusions on neuronal dendrites that receive the majority of excitatory synaptic inputs. They are also the sites where DAG molecules are produced through activation of postsynaptic receptors, including metabotropic glutamate receptors and NMDA receptors. Accumulating evidence indicates that synaptic levels of DAG and PA are important determinants of dendritic spine stability and that the DGKzeta isoform at excitatory postsynaptic sites is critically involved in spine maintenance. In addition, DGKzeta appears to form a multi-protein complex with functionally related proteins to organize efficient DAG and PA signaling pathways at excitatory synapses.


Asunto(s)
Espinas Dendríticas/enzimología , Diacilglicerol Quinasa/metabolismo , Animales , Diglicéridos/metabolismo , Inhibidores Enzimáticos/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
11.
Gastroenterology ; 137(2): 607-17, 617.e1-4, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19642226

RESUMEN

BACKGROUND & AIMS: Vasoactive intestinal polypeptide (VIP) is a principal regulator of fluid and electrolyte secretion in the gastrointestinal system. The VIP type-1 receptor (VPAC1), a class II G-protein-coupled receptor, contains a putative C-terminal PDZ-binding motif. A yeast 2-hybrid screen indicated that the C-terminus of VPAC1 bound to the PDZ domain of synaptic scaffolding molecule (S-SCAM, also known as membrane-associated guanylate kinase inverted-2 [MAGI-2]). We analyzed the association between S-SCAM and VPAC1. METHODS: The biochemical properties and physiologic significance of the interaction between VPAC1 and S-SCAM were examined in heterologous expression systems, T84 colonic epithelial cells, and human pancreas and colon tissues using an integrated molecular and physiologic approach. RESULTS: The physical interaction between VPAC1 and S-SCAM was confirmed by immunoprecipitation in HEK 293 mammalian cells and human pancreatic and colonic tissues. Immunocytochemical analysis indicated that S-SCAM recruited VPAC1 to the junctional area near the apical end of the lateral membrane in T84 cells. Several lines of evidence revealed that S-SCAM inhibits VPAC1 activation. Overexpression of S-SCAM inhibited VPAC1-mediated cAMP production and agonist-induced VPAC1 internalization in HEK 293 and HeLa cells. In addition, S-SCAM decreased the VPAC1-mediated current through the cystic fibrosis transmembrane conductance regulator in Xenopus oocytes, especially at low concentrations of VIP. Importantly, loss of S-SCAM increased VIP-induced short-circuit currents in T84 monolayers, which endogenously express VPAC1 and S-SCAM. CONCLUSIONS: S-SCAM/MAGI-2 interacts with and regulates VPAC1 intracellular localization in epithelial cells and inhibits VPAC1 agonist-induced activation and internalization.


Asunto(s)
Células Epiteliales/metabolismo , Unión Proteica/fisiología , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Análisis de Varianza , Proteínas Portadoras , Comunicación Celular/genética , Comunicación Celular/fisiología , Células Cultivadas , Células Epiteliales/fisiología , Regulación de la Expresión Génica , Guanilato-Quinasas , Humanos , Immunoblotting , Inmunohistoquímica , Probabilidad , Unión Proteica/genética , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/genética , Transducción de Señal/genética , Técnicas del Sistema de Dos Híbridos
12.
Aging Cell ; 19(1): e13081, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31763743

RESUMEN

Alzheimer's disease (AD) is an age-related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD-504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT ) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient-derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau-interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedades Neurodegenerativas/genética , Procesamiento Proteico-Postraduccional/genética , Proteínas tau/metabolismo , Acetilación , Animales , Modelos Animales de Enfermedad , Humanos , Ratones
13.
J Neurosci ; 28(53): 14546-56, 2008 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-19118189

RESUMEN

PSD-95 is an abundant postsynaptic density (PSD) protein involved in the formation and regulation of excitatory synapses and dendritic spines, but the underlying mechanisms are not comprehensively understood. Here we report a novel PSD-95-interacting protein Preso that regulates spine morphogenesis. Preso is mainly expressed in the brain and contains WW (domain with two conserved Trp residues), PDZ (PSD-95/Dlg/ZO-1), FERM (4.1, ezrin, radixin, and moesin), and C-terminal PDZ-binding domains. These domains associate with actin filaments, the Rac1/Cdc42 guanine nucleotide exchange factor betaPix, phosphatidylinositol-4,5-bisphosphate, and the postsynaptic scaffolding protein PSD-95, respectively. Preso overexpression increases the density of dendritic spines in a manner requiring WW, PDZ, FERM, and PDZ-binding domains. Conversely, knockdown or dominant-negative inhibition of Preso decreases spine density, excitatory synaptic transmission, and the spine level of filamentous actin. These results suggest that Preso positively regulates spine density through its interaction with the synaptic plasma membrane, actin filaments, PSD-95, and the betaPix-based Rac1 signaling pathway.


Asunto(s)
Proteínas del Citoesqueleto/fisiología , Espinas Dendríticas/fisiología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Neuronas/ultraestructura , Dominios PDZ/fisiología , Citoesqueleto de Actina/metabolismo , Animales , Células Cultivadas , Chlorocebus aethiops , Cricetinae , Homólogo 4 de la Proteína Discs Large , Embrión de Mamíferos , Expresión Génica/fisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Guanilato-Quinasas , Hipocampo/citología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Modelos Moleculares , Morfogénesis/fisiología , Proteínas del Tejido Nervioso/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Estructura Terciaria de Proteína , Ratas , Transmisión Sináptica/genética , Transfección , Técnicas del Sistema de Dos Híbridos
14.
J Alzheimers Dis ; 70(3): 667-680, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31256134

RESUMEN

Increased levels of total tau (t-tau) and hyperphosphorylated tau (p-tau) proteins in the cerebrospinal fluid of Alzheimer's disease (AD) patients are well documented and strongly correlate with AD pathology. Recent studies have further shown that human tau can be released into the extracellular space and transferred to nascent neurons. However, because the tau protein has no signal peptide identity, the mechanisms underlying its secretion remain poorly understood. In the present study, we confirmed that tau protein secretion was promoted by autophagy inducers and downregulated by beclin1 knockdown or autophagy inhibitors derived from human wild type tau (wt-tau)-overexpressing SH-SY5Y cells. Moreover, both t-tau and p-tau secretion were increased by autophagy activation. Furthermore, we identified that six isoforms of tau protein are secreted in an autophagy-dependent manner. These results indicate that both normal and pathological tau are secreted via an autophagy-mediated secretory pathway in neurons. Understanding this new pathway for tau secretion may provide critical future insights into tau pathologies, such as AD.


Asunto(s)
Enfermedad de Alzheimer , Neuronas/metabolismo , Vías Secretoras/fisiología , Proteínas tau , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/metabolismo , Animales , Autofagia/fisiología , Supervivencia Celular , Células Cultivadas , Ratones , Ovillos Neurofibrilares/metabolismo , Fosforilación , Transporte de Proteínas/fisiología , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/metabolismo
15.
Mol Neurodegener ; 13(1): 2, 2018 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-29338754

RESUMEN

BACKGROUND: Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. To understand the pathological mechanisms underlying AD, developing animal models that completely encompass the main features of AD pathologies is indispensable. Although mouse models that display pathological hallmarks of AD (amyloid plaques, neurofibrillary tangles, or both) have been developed and investigated, a systematic approach for understanding the molecular characteristics of AD mouse models is lacking. METHODS: To elucidate the mechanisms underlying the contribution of amyloid beta (Aß) and tau in AD pathogenesis, we herein generated a novel animal model of AD, namely the AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) mice. The ADLPAPT mice carry three human transgenes, including amyloid precursor protein, presenilin-1, and tau, with six mutations. To characterize the molecular and functional signatures of AD in ADLPAPT mice, we analyzed the hippocampal proteome and performed comparisons with individual-pathology transgenic mice (i.e., amyloid or neurofibrillary tangles) and wild-type mice using quantitative proteomics with 10-plex tandem mass tag. RESULTS: The ADLPAPT mice exhibited accelerated neurofibrillary tangle formation in addition to amyloid plaques, neuronal loss in the CA1 area, and memory deficit at an early age. In addition, our proteomic analysis identified nearly 10,000 protein groups, which enabled the identification of hundreds of differentially expressed proteins (DEPs) in ADLPAPT mice. Bioinformatics analysis of DEPs revealed that ADLPAPT mice experienced age-dependent active immune responses and synaptic dysfunctions. CONCLUSIONS: Our study is the first to compare and describe the proteomic characteristics in amyloid and neurofibrillary tangle pathologies using isobaric label-based quantitative proteomics. Furthermore, we analyzed the hippocampal proteome of the newly developed ADLPAPT model mice to investigate how both Aß and tau pathologies regulate the hippocampal proteome. Because the ADLPAPT mouse model recapitulates the main features of AD pathogenesis, the proteomic data derived from its hippocampus has significant utility as a novel resource for the research on the Aß-tau axis and pathophysiological changes in vivo.


Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide/genética , Modelos Animales de Enfermedad , Presenilina-1/genética , Proteínas tau/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Hipocampo/patología , Humanos , Ratones , Ratones Transgénicos , Mutación , Proteómica/métodos , Transgenes
16.
Mol Neurodegener ; 12(1): 23, 2017 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-28241840

RESUMEN

BACKGROUND: Reduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer's disease (AD) and is recently being considered a possible therapeutic strategy. However, the restoring mechanism of HDAC6 inhibition has not been fully understood. METHODS AND RESULTS: Here, we found that an anti-oxidant protein Peroxdiredoxin1 (Prx1), a substrate of HDAC6, malfunctions in Aß treated cells, the brains of 5xFAD AD model mice and AD patients. Malfunctioning Prx1, caused by reduced Prx1 acetylation levels, was recovered by HDAC6 inhibition. Increasing acetylation levels of Prx1 by HDAC6 inhibition recovered elevated reactive oxygen species (ROS) levels, elevated Ca2+ levels and impaired mitochondrial axonal transport, sequentially, even in the presence of Aß. Prx1 mutant studies on the K197 site for an acetylation mimic or silencing mutation support the results showing that HDAC6 inhibitor restores Aß-induced disruption of ROS, Ca2+ and axonal transport. CONCLUSIONS: Taken together, increasing acetylation of Prx1 by HDAC6 inhibition has several beneficial effects in AD pathology. Here, we present the novel mechanism by which elevated acetylation of Prx1 rescues mitochondrial axonal transport impaired by Aß. Therefore, our results suggest that modulation of Prx1 acetylation by HDAC6 inhibition has great therapeutic potential for AD and has further therapeutic possibilities for other neurodegenerative diseases as well.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Transporte Axonal , Histona Desacetilasas/metabolismo , Peroxirredoxinas/metabolismo , Acetilación/efectos de los fármacos , Enfermedad de Alzheimer/patología , Animales , Western Blotting , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Inmunohistoquímica , Inmunoprecipitación , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Transfección
17.
Food Res Int ; 102: 265-273, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29195948

RESUMEN

This study examined the effects of soil type and fertilizer regimes on variations in fatty acids (FAs) and vitamin E (Vit-E) in 6-year-old ginseng roots. We observed significant variation in both FA and Vit-E contents owing to the type and quantity of organic fertilizer used in each soil type during cultivation. Unsaturated FAs were approximately 2.7-fold higher in ginseng than in saturated FAs. Linoleic, palmitic, and oleic acids were the most abundant FAs detected in ginseng roots. Additionally, α-tocopherol was the major Vit-E detected. In particular, the increased application of rice straw compost or food waste fertilizer elevated the quantity of nutritionally desirable FAs and bioactive Vit-E in ginseng root. Partial least square-discriminant analysis (PLS-DA) score plots showed that soil type might be the main cause of differences in FA and Vit-E levels in ginseng. Specifically, the PLS-DA model indicated that palmitic acid is a suitable FA marker in determining whether ginseng plants were grown in a paddy-converted field or an upland field. Moreover, linoleic acid levels were highly correlated with α-linolenic acid (r=0.8374; p<0.0001) according to Pearson's correlations and hierarchical clustering analysis. Hence, these preliminary results should prove useful for the reliable production of ginseng containing high phytonutrient quantities according to cultivation conditions.


Asunto(s)
Ácidos Grasos/análisis , Fertilizantes/análisis , Panax/química , Raíces de Plantas/química , Suelo/química , Vitamina E/análisis , Ácidos Grasos/química , Vitamina E/química
18.
Sci Rep ; 5: 16410, 2015 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-26553645

RESUMEN

Protein ubiquitination has a significant influence on diverse aspects of neuronal development and function. Dorfin, also known as Rnf19a, is a RING finger E3 ubiquitin ligase implicated in amyotrophic lateral sclerosis and Parkinson's disease, but its in vivo functions have not been explored. We report here that Dorfin is a novel binding partner of the excitatory postsynaptic scaffolding protein PSD-95. Dorfin-mutant (Dorfin(-/-)) mice show reduced adult neurogenesis and enhanced long-term potentiation in the hippocampal dentate gyrus, but normal long-term potentiation in the CA1 region. Behaviorally, Dorfin(-/-) mice show impaired contextual fear conditioning, but normal levels of cued fear conditioning, fear extinction, spatial learning and memory, object recognition memory, spatial working memory, and pattern separation. Using a proteomic approach, we also identify a number of proteins whose ubiquitination levels are decreased in the Dorfin(-/-) brain. These results suggest that Dorfin may regulate adult neurogenesis, synaptic plasticity, and contextual fear memory.


Asunto(s)
Condicionamiento Clásico , Miedo , Guanilato-Quinasas/metabolismo , Potenciación a Largo Plazo/genética , Proteínas de la Membrana/metabolismo , Neurogénesis/genética , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Homólogo 4 de la Proteína Discs Large , Potenciales Postsinápticos Excitadores/genética , Técnicas de Inactivación de Genes , Hipocampo/metabolismo , Homocigoto , Aprendizaje , Memoria , Ratones , Ratones Noqueados , Unión Proteica , Mapeo de Interacción de Proteínas , Proteoma , Proteómica/métodos , Agitación Psicomotora/genética , Técnicas del Sistema de Dos Híbridos
19.
J Biol Chem ; 281(3): 1461-9, 2006 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-16293618

RESUMEN

Na+/H+ exchanger 3 (NHE3) plays a pivotal role in transepithelial Na+ and HCO3(-) absorption across a wide range of epithelia in the digestive and renal-genitourinary systems. Accumulating evidence suggests that PDZ-based adaptor proteins play an important role in regulating the trafficking and activity of NHE3. A search for NHE3-binding modular proteins using yeast two-hybrid assays led us to the PDZ-based adaptor Shank2. The interaction between Shank2 and NHE3 was further confirmed by immunoprecipitation and surface plasmon resonance studies. When expressed in PS120/NHE3 cells, Shank2 increased the membrane expression and basal activity of NHE3 and attenuated the cAMP-dependent inhibition of NHE3 activity. Furthermore, knock-down of native Shank2 expression in Caco-2 epithelial cells by RNA interference decreased NHE3 protein expression as well as activity but amplified the inhibitory effect of cAMP on NHE3. These results indicate that Shank2 is a novel NHE3 interacting protein that is involved in the fine regulation of transepithelial salt and water transport through affecting NHE3 expression and activity.


Asunto(s)
Proteínas del Tejido Nervioso/metabolismo , Intercambiadores de Sodio-Hidrógeno/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Neoplasias del Colon , Cricetinae , Eliminación de Gen , Genes Reporteros , Humanos , Cinética , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Intercambiadores de Sodio-Hidrógeno/química , Intercambiadores de Sodio-Hidrógeno/genética , Resonancia por Plasmón de Superficie , Transfección
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