RESUMEN
BACKGROUND: Lewy body diseases (LBDs), which are pathologically defined as the presence of intraneuronal α-synuclein (α-Syn) inclusions called Lewy bodies, encompass Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies. Autopsy studies have shown that the olfactory bulb (OB) is one of the regions where Lewy pathology develops and initiates its spread in the brain. OBJECTIVE: This study aims to clarify how Lewy pathology spreads from the OB and affects brain functions using nonhuman primates. METHODS: We inoculated α-Syn preformed fibrils into the unilateral OBs of common marmosets (Callithrix jacchus) and performed pathological analyses, manganese-enhanced magnetic resonance imaging, and 18 F-fluoro-2-deoxy-d-glucose positron emission tomography up to 6 months postinoculation. RESULTS: Severe α-Syn pathology was observed within the olfactory pathway and limbic system, while mild α-Syn pathology was seen in a wide range of brain regions, including the substantia nigra pars compacta, locus coeruleus, and even dorsal motor nucleus of the vagus nerve. The brain imaging analyses showed reduction in volume of the OB and progressive glucose hypometabolism in widespread brain regions, including the occipital lobe, and extended beyond the pathologically affected regions. CONCLUSIONS: We generated a novel nonhuman primate LBD model with α-Syn propagation from the OB. This model suggests that α-Syn propagation from the OB is related to OB atrophy and cerebral glucose hypometabolism in LBDs. © 2022 International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Animales , Callithrix/metabolismo , Desoxiglucosa/metabolismo , Glucosa/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Manganeso/metabolismo , Bulbo Olfatorio/metabolismo , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
Parkinson's disease (PD) is characterized by dopaminergic (DA) cell loss and the accumulation of pathological alpha synuclein (asyn), but its precise pathomechanism remains unclear, and no appropriate animal model has yet been established. Recent studies have shown that a heterozygous mutation of glucocerebrosidase (gba) is one of the most important genetic risk factors in PD. To create mouse model for PD, we crossed asyn Bacterial Artificial Chromosome transgenic mice with gba heterozygous knockout mice. These double-mutant (dm) mice express human asyn in a physiological manner through its native promoter and showed an increase in phosphorylated asyn in the regions vulnerable to PD, such as the olfactory bulb and dorsal motor nucleus of the vagus nerve. Only dm mice showed a significant reduction in DA cells in the substantia nigra pars compacta, suggesting these animals were suitable for a prodromal model of PD. Next, we investigated the in vivo mechanism by which GBA insufficiency accelerates PD pathology, focusing on lipid metabolism. Dm mice showed an increased level of glucosylsphingosine without any noticeable accumulation of glucosylceramide, a direct substrate of GBA. In addition, the overexpression of asyn resulted in decreased GBA activity in mice, while dm mice tended to show an even further decreased level of GBA activity. In conclusion, we created a novel prodromal mouse model to study the disease pathogenesis and develop novel therapeutics for PD and also revealed the mechanism by which heterozygous gba deficiency contributes to PD through abnormal lipid metabolism under conditions of an altered asyn expression in vivo.
Asunto(s)
Glucosilceramidasa/genética , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Humanos , Metabolismo de los Lípidos/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Porción Compacta de la Sustancia Negra/metabolismo , Porción Compacta de la Sustancia Negra/patología , Síntomas ProdrómicosRESUMEN
Parkinson's disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson's disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson's disease and a genome-wide association study in Parkinson's disease has identified SNCA as a risk gene for Parkinson's disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson's disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson's disease and a Rep1 polymorphism, all of which are causal of familial Parkinson's disease or increase the risk of sporadic Parkinson's disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson's disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson's disease that showed RBD-like behaviour and hyposmia without motor symptoms.
Asunto(s)
Encéfalo/metabolismo , Modelos Animales de Enfermedad , Ratones , Trastornos del Olfato/genética , Enfermedad de Parkinson/genética , Síntomas Prodrómicos , Trastorno de la Conducta del Sueño REM/genética , alfa-Sinucleína/genética , Animales , Recuento de Células , Cromosomas Artificiales Bacterianos , Electroencefalografía , Electromiografía , Endopeptidasa K/metabolismo , Ratones Transgénicos , Trastornos del Olfato/fisiopatología , Enfermedad de Parkinson/fisiopatología , Polimorfismo de Nucleótido Simple , Trastorno de la Conducta del Sueño REM/fisiopatología , Sueño , alfa-Sinucleína/metabolismoRESUMEN
Oligomer formation and accumulation of pathogenic proteins are key events in the pathomechanisms of many neurodegenerative diseases, such as Alzheimer disease, ALS, and the polyglutamine (polyQ) diseases. The autophagy-lysosome degradation system may have therapeutic potential against these diseases because it can degrade even large oligomers. Although p62/sequestosome 1 plays a physiological role in selective autophagy of ubiquitinated proteins, whether p62 recognizes and degrades pathogenic proteins in neurodegenerative diseases has remained unclear. In this study, to elucidate the role of p62 in such pathogenic conditions in vivo, we used Drosophila models of neurodegenerative diseases. We found that p62 predominantly co-localizes with cytoplasmic polyQ protein aggregates in the MJDtr-Q78 polyQ disease model flies. Loss of p62 function resulted in significant exacerbation of eye degeneration in these flies. Immunohistochemical analyses revealed enhanced accumulation of cytoplasmic aggregates by p62 knockdown in the MJDtr-Q78 flies, similarly to knockdown of autophagy-related genes (Atgs). Knockdown of both p62 and Atgs did not show any additive effects in the MJDtr-Q78 flies, implying that p62 function is mediated by autophagy. Biochemical analyses showed that loss of p62 function delays the degradation of the MJDtr-Q78 protein, especially its oligomeric species. We also found that loss of p62 function exacerbates eye degeneration in another polyQ disease fly model as well as in ALS model flies. We therefore conclude that p62 plays a protective role against polyQ-induced neurodegeneration, by the autophagic degradation of polyQ protein oligomers in vivo, indicating its therapeutic potential for the polyQ diseases and possibly for other neurodegenerative diseases.
Asunto(s)
Autofagia , Proteínas de Drosophila/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Péptidos/química , Células Fotorreceptoras de Invertebrados/metabolismo , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Factor de Transcripción TFIID/metabolismo , Animales , Citoplasma/metabolismo , Drosophila , Inmunohistoquímica , Microscopía Electrónica de Rastreo , Fosforilación , Células Fotorreceptoras de Invertebrados/ultraestructura , Desnaturalización Proteica , Pliegue de Proteína , Transgenes , Proteínas Ubiquitinadas/químicaRESUMEN
This article is part of a Special Issue "Estradiol and cognition". Estradiol (E2) is locally synthesized within the hippocampus and the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. The molecular mechanisms of modulation through the synaptic estrogen receptor (ER) and its downstream signaling, however, are largely unknown in the dentate gyrus (DG). We investigated the E2-induced modulation of dendritic spines in male adult rat hippocampal slices by imaging Lucifer Yellow-injected DG granule cells. Treatments with 1 nM E2 increased the density of spines by approximately 1.4-fold within 2h. Spine head diameter analysis showed that the density of middle-head spines (0.4-0.5 µm) was significantly increased. The E2-induced spine density increase was suppressed by blocking Erk MAPK, PKA, PKC and LIMK. These suppressive effects by kinase inhibitors are not non-specific ones because the GSK-3ß antagonist did not inhibit E2-induced spine increase. The ER antagonist ICI 182,780 also blocked the E2-induced spine increase. Taken together, these results suggest that E2 rapidly increases the density of spines through kinase networks that are driven by synaptic ER.
Asunto(s)
Espinas Dendríticas/fisiología , Giro Dentado/citología , Estradiol/fisiología , Proteínas Quinasas/fisiología , Animales , Recuento de Células , Espinas Dendríticas/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Estradiol/análogos & derivados , Estradiol/farmacología , Antagonistas del Receptor de Estrógeno/farmacología , Fulvestrant , Masculino , Redes y Vías Metabólicas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Ratas , Ratas WistarRESUMEN
Dysregulation of cell proliferation and the cell cycle are associated with various diseases, such as cancer. Cyclin-dependent kinases (CDKs) play central roles in cell proliferation and the cell cycle. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in a restricted range of tissues, including the brain and numerous types of cancer. However, the molecular functions of UCH-L1 remain elusive. In this study, we found that UCH-L1 physically interacts with CDK1, CDK4, and CDK5, enhancing their kinase activity. Using several mutants of UCH-L1, we showed that this enhancement is dependent upon interaction levels between UCH-L1 and CDKs but is independent of the known ubiquitin-related functions of UCH-L1. Gain- and loss-of-function studies revealed that UCH-L1 enhances proliferation of multiple cell types, including human cancer cells. Inhibition of the interaction between UCH-L1 and cell cycle-associated CDK resulted in the abolishment of UCH-L1-induced enhancement of cell proliferation. RNA interference of UCH-L1 reduced the growth of human xenograft tumors in mice. We concluded that UCH-L1 is a novel regulator of the kinase activities of CDKs. We believe that our findings from this study will significantly contribute to our understanding of cell cycle-associated diseases.
Asunto(s)
Proteína Quinasa CDC2/metabolismo , Proliferación Celular , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimología , Ubiquitina Tiolesterasa/metabolismo , Animales , Proteína Quinasa CDC2/genética , Células COS , Chlorocebus aethiops , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 5 Dependiente de la Ciclina/genética , Células HeLa , Humanos , Ratones , Mutación , Células 3T3 NIH , Proteínas de Neoplasias/genética , Trasplante de Neoplasias , Neoplasias/genética , Neoplasias/patología , Trasplante Heterólogo , Ubiquitina Tiolesterasa/genéticaRESUMEN
Accurate 3D determination of postsynaptic structures is essential to our understanding memory-related function and pathology in neurons. However, current methods of spine analysis require time-consuming and labor-intensive manual spine identification in large image data sets. Therefore, a realistic implementation of algorithm is necessary to replace manual identification. Here, we describe a new method for the automated detection of spines and dendrites based on analysis of geometrical features. Our "Spiso-3D" software carries out automated dendrite reconstruction and spine detection using both eigenvalue images and information of brightness, avoiding detection of pseudo-spines. To demonstrate the potential application of Spiso-3D automated analysis, we distinguished the rapid effects of androgen and estrogen on rapid modulation of spine head diameter in the hippocampus. These findings advance our understanding of neurotrophic function of brain sex steroids. Our method is expected to be valuable to analyze vast amounts of dendritic spines in neurons in the mammalian cerebral cortex.
Asunto(s)
Automatización de Laboratorios/métodos , Espinas Dendríticas , Procesamiento de Imagen Asistido por Computador/métodos , Imagenología Tridimensional/métodos , Programas Informáticos , Algoritmos , Andrógenos/farmacología , Animales , Espinas Dendríticas/efectos de los fármacos , Estrógenos/farmacología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Masculino , Microscopía Confocal , Ratas , Ratas WistarRESUMEN
The hippocampus is a center for learning and memory as well as a target of Alzheimer's disease in aged humans. Synaptic modulation by estrogen is essential to understand the molecular mechanisms of estrogen replacement therapy. Because the local synthesis of estrogen occurs in the hippocampus of both sexes, in addition to the estrogen supply from the gonads, its functions are attracting much attention. Hippocampal estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly. Slow actions of 17ß-estradiol (17ß-E2) occur via classical nuclear receptors (ERα or ERß), while rapid E2 actions occur via synapse-localized ERα or ERß. Elevation or decrease of the E2 concentration changes rapidly the density and morphology of spines in CA1-CA3 neurons. ERα, but not ERß, drives this enhancement/suppression of spinogenesis. Kinase networks are involved downstream of ERα. The long-term depression but not the long-term potentiation is modulated rapidly by changes of E2 level. Determination of the E2 concentration in the hippocampus is enabled by mass-spectrometry in combination with derivatization methods. The E2 level in the hippocampus is as high as approx. 8 nM for the male and 0.5-2 nM for the female, which is much higher than that in circulation. Therefore, hippocampus-derived E2 plays a major role in modulation of synaptic plasticity. Many hippocampal slice experiments measure the restorative effects of E2 by supplementation of E2 to E2-depleted slices. Accordingly, isolated slice experiments can be used as in vitro models of in vivo estrogen replacement therapy for ovariectomized female animals with depleted circulating estrogen.
Asunto(s)
Estradiol/metabolismo , Estrógenos/metabolismo , Hipocampo/metabolismo , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Sinapsis/metabolismo , Animales , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Hipocampo/citología , Humanos , Masculino , Neuronas/citologíaRESUMEN
For the development of disease-modifying therapies for Parkinson's disease (PD) the identification of biomarkers in the prodromal stage is urgently required. Because PD is considered a systemic disease even in the early stage, we performed a metabolomic analysis of the plasma from a mouse model of prodromal PD (p-PD). Increased levels of isobutyrylcarnitine in p-PD mice imply an abnormality in ß-oxidation in mitochondria, and increased levels of pyrimidine nucleoside can be associated with mitochondrial dysfunction. Consistent with these results, the immunoblot analysis showed a defect in mitochondrial complex I assembly in p-PD mice. These results suggest that systemic mitochondrial dysfunction may exist in p-PD mice and contribute to the pathogenesis of PD, potentially being useful as early biomarkers for PD.
Asunto(s)
Biomarcadores/sangre , Carnitina/análogos & derivados , Mitocondrias/patología , Trastornos Parkinsonianos/metabolismo , Animales , Carnitina/sangre , Modelos Animales de Enfermedad , Metabolómica , Ratones , Mitocondrias/metabolismo , Síntomas ProdrómicosRESUMEN
Retinal degeneration is a progressive retinal damage in ocular vascular diseases. There are several reasons for this, such as occlusion of arteries or veins, diabetic retinopathy, or hereditary retinal diseases. To study pathological mechanisms of retinal degeneration, it is required to develop experimentally reproducible and clinically relevant models. In our previous studies, we developed a murine model of retinal hypoperfusion by unilateral common carotid artery occlusion (UCCAO) which mimics the pathophysiology of ocular ischemic syndrome (OIS) in humans, and described broad pathological mechanisms in the retina after UCCAO. However, there still remain missing pieces of the ocular pathologic process by UCCAO. In this study, we examined those unfound mechanisms. UCCAO was performed on adult mice. Ocular dysfunctions, histological deficits, and inflammation were examined after UCCAO, compared with sham-operated mice. Evaluation values were analyzed by electrophysiological, histological, and molecular biological methods. Eyelid drooping was permanently seen after UCCAO. Induction time point of acute reversible cataract under anesthesia was shortened. Retinal/visual dysfunctions were detected 2-4 weeks after UCCAO. Specifically, scotopic b-wave was more affected than a-wave, with the dysfunction of photopic b-wave. Impaired oscillatory potentials and visual evoked potential were constantly observed. Pathological Müller gliosis/inflammation was featured with NeuN-positive cell loss in the ganglion cell layer. Axial length, intraocular pressure, pupillary light reflex, and retinal pigment epithelium/choroidal thickness were not changed by UCCAO. A murine model of retinal ischemia by UCCAO can be useful for studying a series of degenerative process in the ischemic retina.
Asunto(s)
Arteriopatías Oclusivas/patología , Enfermedades de las Arterias Carótidas/patología , Arteria Carótida Común/patología , Isquemia/patología , Retina/patología , Degeneración Retiniana/patología , Animales , Modelos Animales de Enfermedad , Potenciales Evocados Visuales/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Células Ganglionares de la Retina/patologíaRESUMEN
Modulation of hippocampal synaptic plasticity by androgen has been attracting much attention. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. Here we demonstrated rapid effects of dihydrotestosterone (DHT) and testosterone (T) on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. The application of 10nM DHT or T induced rapid increase in the density of thorns within 2h. The androgen-mediated increase was suppressed by blocking several kinases, such as Erk MAPK, p38 MAPK, PKC, and CaMKII. On the other hand, PKA, PI3K were not involved in the signaling of thorn-genesis. The increase in the thorn density by androgen was also blocked by the inhibitor of classical androgen receptor. Almost no difference was observed between DHT and T in the effect on the thorn density. We observed that the androgen-induced thorn-genesis is opposite to estrogen-induced thorn-degeneration.
Asunto(s)
Andrógenos/fisiología , Dendritas/fisiología , Hipocampo/fisiología , Andrógenos/farmacología , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Dendritas/efectos de los fármacos , Dihidrotestosterona/metabolismo , Dihidrotestosterona/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hipocampo/citología , Hipocampo/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Wistar , Testosterona/farmacología , Testosterona/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The original article [1] mistakenly omitted essential information regarding Fig. 1c; thus, the authors would like to note that Fig. 1c describes transmission electron microscopy of α-Syn PFFs before sonication.
RESUMEN
Estrogen and androgen are synthesized from cholesterol locally in hippocampal neurons of adult animals. These neurosteroids are synthesized by cytochrome P450s and hydroxysteroid dehydrogenases (HSDs) and 5alpha-reductase. The expression levels of enzymes are as low as 1/200-1/50,000 of those in endocrine organs, however these numbers are high enough for local synthesis. Localization of P450(17alpha), P450arom, 17beta-HSD and 5alpha-reductase is observed in principal glutamatergic neurons in CA1, CA3 and the dendate gyrus. Several nanomolar levels of estrogen and androgen are observed in the hippocampus. Estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly in the hippocampus. Rapid action of 17beta-estradiol via membrane receptors is demonstrated for spinogenesis and long-term depression (LTD). The enhancement of LTD by 1-10nM estradiol occurs within 1 h. The density of spine is increased in CA1 pyramidal neurons within 2h after application of estradiol. The density of spine-like structure is, however, decreased by estradiol in CA3 pyramidal neurons. ERalpha, but not ERbeta, induces the same enhancement/suppression effects on both spinogenesis and LTD.
Asunto(s)
Encéfalo/metabolismo , Estrógenos/biosíntesis , Memoria , Plasticidad Neuronal , Sinapsis/metabolismo , Animales , Encéfalo/ultraestructura , Humanos , Sinapsis/ultraestructuraRESUMEN
BACKGROUND: Intraneuronal α-synuclein (α-Syn) aggregates known as Lewy bodies (LBs) and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the pathological hallmarks of Parkinson's disease (PD). Braak's hypothesis based on autopsy studies suggests that Lewy pathology initially occurs in the enteric nervous system (ENS) and then travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX), proceeding from there in a caudo-rostral direction. Recent evidence that α-Syn aggregates propagate between interconnected neurons supports this hypothesis. However, there is no direct evidence demonstrating this transmission from the ENS to the dmX and then to the SNpc. METHODS: We inoculated α-Syn preformed fibrils (PFFs) or phosphate-buffered saline (PBS) into the mouse gastric wall and analyzed the progression of the pathology. RESULTS: The mice inoculated with α-Syn PFFs, but not with PBS, developed phosphorylated α-Syn (p-α-Syn)-positive LB-like aggregates in the dmX at 45 days postinoculation. This aggregate formation was completely abolished when vagotomy was performed prior to inoculation of α-Syn PFFs, suggesting that the aggregates in the dmX were retrogradely induced via the vagus nerve. Unexpectedly, the number of neurons containing p-α-Syn-positive aggregates in the dmX decreased over time, and no further caudo-rostral propagation beyond the dmX was observed up to 12 months postinoculation. P-α-Syn-positive aggregates were also present in the myenteric plexus at 12 months postinoculation. However, unlike in patients with PD, there was no cell-type specificity in neurons containing those aggregates in this model. CONCLUSIONS: These results indicate that α-Syn PFF inoculation into the mouse gastrointestinal tract can induce α-Syn pathology resembling that of very early PD, but other factors are apparently required if further progression of PD pathology is to be replicated in this animal model.
Asunto(s)
Tronco Encefálico/patología , Tracto Gastrointestinal/metabolismo , Nervio Vago/metabolismo , alfa-Sinucleína/metabolismo , Animales , Cuerpos de Lewy/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad de Parkinson , Transporte de Proteínas/fisiologíaRESUMEN
Adverse maternal environment during gestation and lactation can have negative effects on the developing brain that persist into adulthood and result in behavioral impairment. Recent studies of human and animal models suggest epidemiological and experimental association between disturbances in maternal environments during brain development and the occurrence of neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, anxiety, depression, and neurodegenerative diseases. In this review, we summarize recent advances in understanding the effects of maternal metabolic and hormonal abnormalities on the developing brain by focusing on the dynamics of dendritic spine, an excitatory postsynaptic structure. We discuss the abnormal instability of dendritic spines that is common to developmental disorders and neurological diseases. We also introduce our recent studies that demonstrate how maternal obesity and hyperandrogenism leads to abnormal development of neuronal circuitry and persistent synaptic instability, which results in the loss of synapses. The aim of this review is to highlight the links between abnormal maternal environment, behavioral impairment in offspring, and the dendiric spine pathology of neuropsychiatric disorders.
RESUMEN
Maternal obesity has negative effects on the neurodevelopment of the offspring. Pups from high-fat diet (HFD)-fed mice exhibit peroxidized lipid accumulations in the brain and behavioral impairments. However, the synaptic basis of maternal HFD-induced brain dysfunction in offspring remains unclear. In the present study, we focused on the dynamics and morphology of postsynaptic dendritic spines and filopodia in the offspring of HFD-fed mouse dams, using in vivo two-photon imaging, chosen because of the involvement of peripheral organs and non-neuronal cells in the abnormal metabolic state. We observed instability of dendritic spines and filopodia in the cerebral cortex of offspring from HFD-fed dams. Interestingly, the synaptic instability persisted into adulthood with a lower spine density even when the offspring were fed with a normal diet after weaning. HFD-fed offspring from HFD-fed dams showed a severe disruption of dendritic spines. Synaptic instability and loss of spines were caused even by HFD exposure exclusively during lactation. The treatment of ascorbic acid, an antioxidant, during lactation ameliorated the synaptic impairments. These results suggest that maternal obesity leads to persistent synaptic impairments in the offspring, which may be associated with behavioral deficits in adulthood, and that these synaptic deficits may be due to oxidative stress from peroxidized lipid accumulations during the lactation period.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Lactancia/metabolismo , Estrés Oxidativo/fisiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Sinapsis/metabolismo , Animales , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Dieta Alta en Grasa/tendencias , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/patología , Sinapsis/patologíaRESUMEN
Fetal brain development is programmed by the maternal intrauterine environment, and disturbance of the in utero environment leads to persisting deficits in brain functions of the offspring. Testosterone is an intrauterine environmental factor, and plays significant roles in fetal development. From human and animal model studies, it has been suggested that increased intrauterine testosterone concentration triggers subsequent autistic-like behavior of the offspring; however, the effects of maternal excess testosterone on synaptic development of the offspring remain unknown. In the present study, we employed prenatally testosterone-exposed mice, and by using in vivo two-photon imaging, we analyzed the dynamics, density, and morphology of the dendritic spine, an excitatory postsynaptic structure. We found that the offspring from testosterone-treated dams showed abnormal synaptic instability persisting into young adulthood, whereas dendritic spines in control mice became stabilized with normal synaptic maturation. In prenatally testosterone-exposed mice, the density of dendritic spines was excessively increased, and their morphology was abnormal. These results suggest that prenatally testosterone-exposed mice may have deficits in synaptic development, and furthermore that the observed pathological features of their dendritic spines may be the cause of the synaptic pathogenesis in prenatally testosterone-exposed mice.
Asunto(s)
Espinas Dendríticas/patología , Efectos Tardíos de la Exposición Prenatal , Testosterona/administración & dosificación , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , EmbarazoRESUMEN
Late-onset neurodegenerative diseases are characterized by neurological symptoms and progressive neuronal death. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, causes the symptoms of neurodegenerative diseases. However, the mechanisms underlying the dysfunction that occurs prior to cell death remain unclear. To investigate the synaptic basis of this dysfunction, we employed in vivo two-photon imaging to analyse excitatory postsynaptic dendritic protrusions. We used Sca1(154Q/2Q) mice, an established knock-in mouse model of the polyglutamine disease spinocerebellar ataxia type 1 (SCA1), which replicates human SCA1 features including ataxia, cognitive impairment, and neuronal death. We found that Sca1(154Q/2Q) mice exhibited greater synaptic instability than controls, without synaptic loss, in the cerebral cortex, where obvious neuronal death is not observed, even before the onset of distinct symptoms. Interestingly, this abnormal synaptic instability was evident in Sca1(154Q/2Q) mice from the synaptic developmental stage, and persisted into adulthood. Expression of synaptic scaffolding proteins was also lower in Sca1(154Q/2Q) mice than controls before synaptic maturation. As symptoms progressed, synaptic loss became evident. These results indicate that aberrant synaptic instability, accompanied by decreased expression of scaffolding proteins during synaptic development, is a very early pathology that precedes distinct neurological symptoms and neuronal cell death in SCA1.
Asunto(s)
Ataxina-1/genética , Ataxias Espinocerebelosas/patología , Sinapsis/metabolismo , Animales , Ataxina-1/metabolismo , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/patología , Corteza Cerebral/metabolismo , Dendritas/metabolismo , Dendritas/patología , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal , Microscopía de Fluorescencia por Excitación Multifotónica , Proteínas Nucleares/metabolismo , Ataxias Espinocerebelosas/metabolismo , Factores de TiempoRESUMEN
Rapid modulation of hippocampal synaptic plasticity by locally synthesized androgen is important in addition to circulating androgen. Here, we investigated the rapid changes of dendritic spines in response to the elevation of dihydrotestosterone (DHT) and testosterone (T), by using hippocampal slices from adult male rats, in order to clarify whether these signaling processes include synaptic/extranuclear androgen receptor (AR) and activation of kinases. We found that the application of 10nM DHT and 10nM T increased the total density of spines by approximately 1.3-fold within 2h, by imaging Lucifer Yellow-injected CA1 pyramidal neurons. Interestingly, DHT and T increased different head-sized spines. While DHT increased middle- and large-head spines, T increased small-head spines. Androgen-induced spinogenesis was suppressed by individually blocking Erk MAPK, PKA, PKC, p38 MAPK, LIMK or calcineurin. On the other hand, blocking CaMKII did not inhibit spinogenesis. Blocking PI3K altered the spine head diameter distribution, but did not change the total spine density. Blocking mRNA and protein synthesis did not suppress the enhancing effects induced by DHT or T. The enhanced spinogenesis by androgens was blocked by AR antagonist, which AR was localized postsynaptically. Taken together, these results imply that enhanced spinogenesis by DHT and T is mediated by synaptic/extranuclear AR which rapidly drives the kinase networks. This article is part of a Special Issue entitled SI: Brain and Memory.
Asunto(s)
Andrógenos/fisiología , Región CA1 Hipocampal/fisiología , Espinas Dendríticas/fisiología , Dihidrotestosterona/farmacología , Sinapsis/fisiología , Testosterona/fisiología , Andrógenos/farmacología , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas , Masculino , Ratas , Ratas Wistar , Receptores Androgénicos/fisiología , Sinapsis/efectos de los fármacos , Testosterona/farmacologíaRESUMEN
Lysosomes contain various hydrolases that can degrade proteins, lipids, nucleic acids and carbohydrates. We recently discovered "RNautophagy," an autophagic pathway in which RNA is directly taken up by lysosomes and degraded. A lysosomal membrane protein, LAMP2C, a splice variant of LAMP2, binds to RNA and acts as a receptor for this pathway. In the present study, we show that DNA is also directly taken up by lysosomes and degraded. Like RNautophagy, this autophagic pathway, which we term "DNautophagy," is dependent on ATP. The cytosolic sequence of LAMP2C also directly interacts with DNA, and LAMP2C functions as a receptor for DNautophagy, in addition to RNautophagy. Similarly to RNA, DNA binds to the cytosolic sequences of fly and nematode LAMP orthologs. Together with the findings of our previous study, our present findings suggest that RNautophagy and DNautophagy are evolutionarily conserved systems in Metazoa.