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1.
Cells ; 10(12)2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34944035

RESUMEN

Mitochondria play a critical role in providing energy, maintaining cellular metabolism, and regulating cell survival and death. To carry out these crucial functions, mitochondria employ more than 1500 proteins, distributed between two membranes and two aqueous compartments. An extensive network of dedicated proteins is engaged in importing and sorting these nuclear-encoded proteins into their designated mitochondrial compartments. Defects in this fundamental system are related to a variety of pathologies, particularly engaging the most energy-demanding tissues. In this review, we summarize the state-of-the-art knowledge about the mitochondrial protein import machinery and describe the known interrelation of its failure with age-related neurodegenerative and cardiovascular diseases.


Asunto(s)
Envejecimiento/metabolismo , Enfermedades Cardiovasculares/metabolismo , Proteínas Mitocondriales/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Animales , Humanos , Membranas Mitocondriales/metabolismo , Transporte de Proteínas
2.
Int J Biol Macromol ; 193(Pt A): 838-846, 2021 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-34728300

RESUMEN

Discovery of robust, selective and specific biomarkers are important for early diagnosis and monitor progression of human diseases. Eye being a common target for several human diseases, vision impediment and complications are often associated with systemic and ocular diseases. Tears are bodily fluids that are closest to eye and are rich in protein content and other metabolites. As a biomarker repository, it advantages over other bodily fluids due to the ability to collect it non-invasively. In this review, we highlight some recent advancements in identification of tear-based protein biomarkers like lacryglobin and cystatin SA for cancer; interleukin-6 and immunoglobulin-A antibody for COVID-19; tau, amyloid-ß-42 and lysozyme-C for Alzheimer's disease; peroxiredoxin-6 and α-synuclein for Parkinson's disease; kallikrein, angiotensin converting enzyme and lipocalin-1 for glaucoma; lactotransferrin and lipophilin-A for diabetic retinopathy and zinc-alpha-2 glycoprotein-1, prolactin and calcium binding protein-A4 for eye thyroid disease. We also discussed identification of tear based non-protein biomarkers like lysophospholipids and acetylcarnitine for glaucoma, 8-hydroxy-2'-deoxyquanosine and malondialdehyde for thyroid eye disease. We elucidate technological advancement in developing tear-based biosensors for diagnosis and monitoring diseases such as diabetes, diabetic retinopathy and Alzheimer's disease. Altogether, the study of tears as potential biomarkers for early diagnosis of human diseases is promising.


Asunto(s)
Biomarcadores de Tumor/metabolismo , COVID-19 , Detección Precoz del Cáncer , Oftalmopatías , Enfermedades Neurodegenerativas , SARS-CoV-2/metabolismo , Lágrimas/metabolismo , COVID-19/diagnóstico , COVID-19/metabolismo , Oftalmopatías/diagnóstico , Oftalmopatías/metabolismo , Humanos , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/metabolismo
3.
Int J Mol Sci ; 22(19)2021 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-34639067

RESUMEN

All eukaryotic cells are composed of the cytoskeleton, which plays crucial roles in coordinating diverse cellular functions such as cell division, morphology, migration, macromolecular stabilization, and protein trafficking. The cytoskeleton consists of microtubules, intermediate filaments, and actin filaments. Cofilin, an actin-depolymerizing protein, is indispensable for regulating actin dynamics in the central nervous system (CNS) development and function. Cofilin activities are spatiotemporally orchestrated by numerous extra- and intra-cellular factors. Phosphorylation at Ser-3 by kinases attenuate cofilin's actin-binding activity. In contrast, dephosphorylation at Ser-3 enhances cofilin-induced actin depolymerization. Cofilin functions are also modulated by various binding partners or reactive oxygen species. Although the mechanism of cofilin-mediated actin dynamics has been known for decades, recent research works are unveiling the profound impacts of cofilin dysregulation in neurodegenerative pathophysiology. For instance, oxidative stress-induced increase in cofilin dephosphorylation is linked to the accumulation of tau tangles and amyloid-beta plaques in Alzheimer's disease. In Parkinson's disease, cofilin activation by silencing its upstream kinases increases α-synuclein-fibril entry into the cell. This review describes the molecular mechanism of cofilin-mediated actin dynamics and provides an overview of cofilin's importance in CNS physiology and pathophysiology.


Asunto(s)
Factores Despolimerizantes de la Actina/metabolismo , Sistema Nervioso Central/fisiología , Susceptibilidad a Enfermedades , Degeneración Nerviosa/etiología , Degeneración Nerviosa/metabolismo , Transducción de Señal , Factores Despolimerizantes de la Actina/genética , Animales , Axones/metabolismo , Proteínas Portadoras/metabolismo , Humanos , Trastornos Mentales/etiología , Trastornos Mentales/metabolismo , Familia de Multigenes , Degeneración Nerviosa/patología , Regeneración Nerviosa , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Plasticidad Neuronal , Unión Proteica , Especies Reactivas de Oxígeno/metabolismo
4.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-34639106

RESUMEN

Animal models of human neurodegenerative disease have been investigated for several decades. In recent years, zebrafish (Danio rerio) and medaka (Oryzias latipes) have become popular in pathogenic and therapeutic studies about human neurodegenerative diseases due to their small size, the optical clarity of embryos, their fast development, and their suitability to large-scale therapeutic screening. Following the emergence of a new generation of molecular biological technologies such as reverse and forward genetics, morpholino, transgenesis, and gene knockout, many human neurodegenerative disease models, such as Parkinson's, Huntington's, and Alzheimer's, were constructed in zebrafish and medaka. These studies proved that zebrafish and medaka genes are functionally conserved in relation to their human homologues, so they exhibit similar neurodegenerative phenotypes to human beings. Therefore, fish are a suitable model for the investigation of pathologic mechanisms of neurodegenerative diseases and for the large-scale screening of drugs for potential therapy. In this review, we summarize the studies in modelling human neurodegenerative diseases in zebrafish and medaka in recent years.


Asunto(s)
Modelos Animales de Enfermedad , Enfermedades Neurodegenerativas/patología , Oryzias/genética , Pez Cebra/genética , Animales , Humanos , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Especificidad de la Especie
5.
Life Sci ; 285: 120006, 2021 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-34606852

RESUMEN

Neurodegenerative diseases (NDDs) are the most common life-threatening disease of the central nervous system and it cause the progressive loss of neuronal cells. The exact mechanism of the disease's progression is not clear and thus line of treatment for NDDs is a baffling issue. During the progression of NDDs, oxidative stress and DNA damage play an important regulatory function, and ultimately induces neurodegeneration. Recently, aberrant cell cycle events have been demonstrated in the progression of different NDDs. However, the pertinent role of signaling mechanism, for instance, post-translational modifications, oxidative stress, DNA damage response pathway, JNK/p38 MAPK, MEK/ERK cascade, actively participated in the aberrant cell cycle reentry induced neuronal cell death. Mounting evidence has demonstrated that aberrant cell cycle re-entry is a major contributing factor in the pathogenesis of NDDs rather than a secondary phenomenon. In the brain of AD patients with mild cognitive impairment, post miotic cell division can be seen in the early stage of the disease. However, in the brain of PD patients, response to various neurotoxic signals, the cell cycle re-entry has been observed that causes neuronal apoptosis. On contrary, the contributing factors that leads to the induction of cell cycle events in mature neurons in HD and ALS brain pathology is remain unclear. Various pharmacological drugs have been developed to reduce the pathogenesis of NDDs, but they are still not helpful in eliminating the cause of these NDDs.


Asunto(s)
Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/metabolismo , Mitosis , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/metabolismo , Neuronas/patología , Acetilación , Animales , Histona Desacetilasas/metabolismo , Humanos , Ubiquitina-Proteína Ligasas/metabolismo
6.
ACS Chem Neurosci ; 12(21): 3972-3984, 2021 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-34652126

RESUMEN

Disrupted cellular trafficking and transport processes are hallmarks of many neurodegenerative disorders (NDs). Recently, efforts have been made toward developing and implementing experimental platforms to identify small molecules that may help restore normative trafficking functions. There have been a number of successes in targeting endomembrane trafficking with the identification of compounds that restore cell viability through rescue of protein transport and trafficking. Here, we describe some of the experimental platforms implemented for small molecule screening efforts for rescue of trafficking defects in neurodegeneration. A survey of phenotypically active small molecules identified to date is provided, including a summary of medicinal chemistry efforts and insights into putative targets and mechanisms of action. In particular, emphasis is put on ligands that demonstrate activity in more than one model of neurodegeneration as retention of phenotypic activity across ND models suggests conservation of biological targets across NDs.


Asunto(s)
Endosomas , Enfermedades Neurodegenerativas , Transporte Biológico , Endosomas/metabolismo , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Transporte de Proteínas
7.
Int J Mol Sci ; 22(19)2021 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-34638645

RESUMEN

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptin's effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptin's actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS, we assessed the mRNA and protein expression profiles of leptin, the long-form of the leptin receptor (Ob-Rb), and leptin-related signaling pathways at two different stages of the disease (onset and end-stage) in TDP-43A315T mice compared to age-matched WT littermates. In addition, at selected time-points, an immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines resistin and leptin, and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon-like peptide 1 (GLP-1), insulin and glucagon) in TDP-43A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Leptina/metabolismo , Transducción de Señal/fisiología , Adipoquinas/metabolismo , Animales , Humanos , Masculino , Ratones , Neuronas Motoras/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Médula Espinal/metabolismo
8.
Int J Mol Sci ; 22(19)2021 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-34638697

RESUMEN

BACKGROUND: The prevention of age-related neurodegenerative disorders is an important issue in an aging society. Microglia-mediated neuroinflammation resulting in dopaminergic neuron loss may lead to the pathogenesis of Parkinson's disease (PD). Lipopolysaccharide (LPS), an endotoxin, induces neuroinflammatory microglial activation, contributing to dopaminergic neuron damage. Diosgenin is a phytosteroid sapogenin with a wide spectrum of pharmacological activities, e.g., anti-inflammatory activity. However, the preventive effect of diosgenin on neuroinflammation is not clear. Thus, in this study, we further investigated the neuroprotective effect of diosgenin on LPS-induced neural damage in vitro and in vivo. METHODS: For in vitro experiments, primary mesencephalic neuron-glia cultures and primary microglia cultures isolated from Sprague-Dawley rats were used. Cells were pretreated with diosgenin and then stimulated with LPS. The expression of proinflammatory cytokines or tyrosine hydroxylase (TH) in the cells was analyzed. In vivo, rats were fed a diet containing 0.1% (w/w) diosgenin for 4 weeks before being administered a unilateral substantia nigra (SN) injection of LPS. Four weeks after the LPS injection, the rats were assessed for lesion severity using the amphetamine-induced rotation test and TH immunohistochemistry. RESULTS: Diosgenin pretreatment prevented LPS-induced neurite shortening in TH-positive neurons in mesencephalic neuron-glia cultures. In addition, pretreatment of primary microglia with diosgenin significantly reduced tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression. Moreover, diosgenin pretreatment significantly suppressed LPS-induced extracellular signal-regulated kinase (ERK) activation. In vivo, the intranigral injection of LPS in rats fed a diosgenin-containing diet significantly improved motor dysfunction and reduced TH expression in SN. CONCLUSION: These results support the effectiveness of diosgenin in protecting dopaminergic neurons from LPS-induced neuroinflammation.


Asunto(s)
Diosgenina/farmacología , Neuronas Dopaminérgicas/metabolismo , Lipopolisacáridos/toxicidad , Microglía/metabolismo , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores/farmacología , Animales , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Neuritas/metabolismo , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/prevención & control , Ratas , Ratas Sprague-Dawley
9.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-34638890

RESUMEN

Extracellular vesicles (EVs) are composed of lipid bilayer membranes and contain various molecules, such as mRNA and microRNA (miRNA), that regulate the functions of the recipient cell. Recent studies have reported the importance of EV-mediated intercellular communication in the brain. The brain contains several types of cells, including neurons and glial cells. Among them, astrocytes are the most abundant glial cells in the mammalian brain and play a wide range of roles, from structural maintenance of the brain to regulation of neurotransmission. Furthermore, since astrocytes can take up EVs, it is possible that EVs originating from inside and outside the brain affect astrocyte function, which in turn affects brain function. However, it has not been fully clarified whether the specific targeting mechanism of EVs to astrocytes as recipient cells exists. In recent years, EVs have attracted attention as a cell-targeted therapeutic approach in various organs, and elucidation of the targeting mechanism of EVs to astrocytes may pave the way for new therapies for brain diseases. In this review, we focus on EVs in the brain that affect astrocyte function and discuss the targeting mechanism of EVs to astrocytes.


Asunto(s)
Astrocitos/metabolismo , Encéfalo/metabolismo , Vesículas Extracelulares/metabolismo , Microglía/metabolismo , Neuronas/metabolismo , Animales , Astrocitos/citología , Encéfalo/citología , Vesículas Extracelulares/genética , Humanos , MicroARNs/genética , Microglía/citología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Neuronas/citología , ARN Mensajero/genética
10.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-34638979

RESUMEN

Neurodegenerative diseases represent a major public health issue and require better therapeutic management. The treatments developed mainly target neuronal activity. However, an inflammatory component must be considered, and microglia may constitute an important therapeutic target. Given the difficulty in developing molecules that can cross the blood-brain barrier, the use of food-derived molecules may be an interesting therapeutic avenue. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (22:6 omega-3), has an inhibitory action on cell death and oxidative stress induced in the microglia. It also acts on the inflammatory activity of microglia. These data obtained in vitro or on animal models are corroborated by clinical trials showing a protective effect of DHA. Whereas DHA crosses the blood-brain barrier, nutritional intake lacks specificity at both the tissue and cellular level. Nanomedicine offers new tools which favor the delivery of DHA at the cerebral level, especially in microglial cells. Because of the biological activities of DHA and the associated nanotargeting techniques, DHA represents a therapeutic molecule of interest for the treatment of neurodegenerative diseases.


Asunto(s)
Suplementos Dietéticos , Ácidos Docosahexaenoicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Microglía/metabolismo , Nanopartículas/química , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Sustancias Protectoras/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/dietoterapia , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Enfermedades Neurodegenerativas/dietoterapia , Estrés Oxidativo/efectos de los fármacos , Resultado del Tratamiento
11.
Isr Med Assoc J ; 23(10): 665-669, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34672451

RESUMEN

BACKGROUND: An arginine-rich apolipoprotein was discovered 50 years ago and became known as apolipoprotein E (ApoE) 10 years later. ApoE is associated with triglyceride-rich lipoproteins and mediates the clearance of these lipoproteins from the plasma. The ApoE-deficient hypercholesterolemic mice are an excellent platform for experimental atherosclerosis because they are similar to human pathology with regard to an atherogenic diet. ApoE is mainly produced in the liver and central nervous system cells. Three alleles determine six ApoE phenotypes with different metabolic effects and plasma cholesterol levels. Type III dysbetalipoproteinemia is associated with wide-spread atherogenesis with a defective ApoE2 resulting in delayed clearance of triglyceride-rich lipoproteins. ApoE4 substantially increases the risk including age of onset, progression, and prognosis of Alzheimer's disease. Therefore, much effort has been directed to the elucidation of the pathogenic role of ApoE related to amyloid ß (Aß) acquisition in the brain. The ApoE trail passing from an enigmatic protein to a major player in cardiovascular and neurodegenerative disorders is reviewed.


Asunto(s)
Apolipoproteínas E/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Animales , Humanos , Factores de Riesgo
12.
Biochem Pharmacol ; 193: 114809, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34673016

RESUMEN

Herein we trace links between biochemical pathways, pathogenesis, and metabolic diseases to set the stage for new therapeutic advances. Cellular and acellular microorganisms including bacteria and viruses are primary pathogenic drivers that cause disease. Missing from this statement are subcellular compartments, importantly mitochondria, which can be pathogenic by themselves, also serving as key metabolic disease intermediaries. The breakdown of food molecules provides chemical energy to power cellular processes, with mitochondria as powerhouses and ATP as the principal energy carrying molecule. Most animal cell ATP is produced by mitochondrial synthase; its central role in metabolism has been known for >80 years. Metabolic disorders involving many organ systems are prevalent in all age groups. Progressive pathogenic mitochondrial dysfunction is a hallmark of genetic mitochondrial diseases, the most common phenotypic expression of inherited metabolic disorders. Confluent genetic, metabolic, and mitochondrial axes surface in diabetes, heart failure, neurodegenerative disease, and even in the ongoing coronavirus pandemic.


Asunto(s)
COVID-19/metabolismo , Enfermedades Metabólicas/metabolismo , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Animales , COVID-19/terapia , Dieta Saludable , Metabolismo Energético/fisiología , Humanos , Enfermedades Metabólicas/terapia , Enfermedades Mitocondriales/terapia , Enfermedades Neurodegenerativas/terapia , Estrés Oxidativo/fisiología
13.
Molecules ; 26(20)2021 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-34684847

RESUMEN

Brain G-protein coupled receptors have been hypothesized to be potential targets for maintaining or restoring cognitive function in normal aged individuals or in patients with neurodegenerative disease. A number of recent reports suggest that activation of melanocortin receptors (MCRs) in the brain can significantly improve cognitive functions of normal rodents and of different rodent models of the Alzheimer's disease. However, the potential impact of normative aging on the expression of MCRs and their potential roles for modulating cognitive function remains to be elucidated. In the present study, we first investigated the expression of these receptors in six different brain regions of young (6 months) and aged (23 months) rats following assessment of their cognitive status. Correlation analysis was further performed to reveal potential contributions of MCR subtypes to spatial learning and memory. Our results revealed statistically significant correlations between the expression of several MCR subtypes in the frontal cortex/hypothalamus and the hippocampus regions and the rats' performance in spatial learning and memory only in the aged rats. These findings support the hypothesis that aging has a direct impact on the expression and function of MCRs, establishing MCRs as potential drug targets to alleviate aging-induced decline of cognitive function.


Asunto(s)
Envejecimiento/metabolismo , Cognición/fisiología , Lóbulo Frontal/metabolismo , Hipotálamo/metabolismo , Receptores de Melanocortina/metabolismo , Animales , Aprendizaje/fisiología , Masculino , Memoria/fisiología , Enfermedades Neurodegenerativas/metabolismo , Ratas , Ratas Endogámicas F344
14.
Int J Mol Sci ; 22(17)2021 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-34502501

RESUMEN

Nrf2 is a basic region leucine-zipper transcription factor that plays a pivotal role in the coordinated gene expression of antioxidant and detoxifying enzymes, promoting cell survival in adverse environmental or defective metabolic conditions. After synthesis, Nrf2 is arrested in the cytoplasm by the Kelch-like ECH-associated protein 1 suppressor (Keap1) leading Nrf2 to ubiquitin-dependent degradation. One Nrf2 activation mechanism relies on disconnection from the Keap1 homodimer through the oxidation of cysteine at specific sites of Keap1. Free Nrf2 enters the nucleus, dimerizes with small musculoaponeurotic fibrosarcoma proteins (sMafs), and binds to the antioxidant response element (ARE) sequence of the target genes. Since oxidative stress, next to neuroinflammation and mitochondrial dysfunction, is one of the hallmarks of neurodegenerative pathologies, a molecular intervention into Nrf2/ARE signaling and the enhancement of the transcriptional activity of particular genes are targets for prevention or delaying the onset of age-related and inherited neurogenerative diseases. In this study, we review evidence for the Nrf2/ARE-driven pathway dysfunctions leading to various neurological pathologies, such as Alzheimer's, Parkinson's, and Huntington's diseases, as well as amyotrophic lateral sclerosis, and the beneficial role of natural and synthetic molecules that are able to interact with Nrf2 to enhance its protective efficacy.


Asunto(s)
Elementos de Respuesta Antioxidante/fisiología , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedad de Alzheimer/genética , Elementos de Respuesta Antioxidante/genética , Antioxidantes/metabolismo , Humanos , Enfermedad de Huntington/genética , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/fisiología , Enfermedades Neurodegenerativas/fisiopatología , Estrés Oxidativo/fisiología , Transducción de Señal/fisiología
15.
ACS Chem Neurosci ; 12(19): 3497-3515, 2021 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-34503333

RESUMEN

Voltage-dependent anion channels (VDACs) of the outer mitochondrial membrane are known conventionally as metabolite flux proteins. However, research findings in the past decade have revealed the multifaceted regulatory roles of VDACs, from governing cellular physiology and mitochondria-mediated apoptosis to directly regulating debilitating cancers and neurodegenerative diseases. VDACs achieve these diverse functions by establishing isoform-dependent stereospecific interactomes in the cell with the cytosolic constituents and endoplasmic reticulum complexes, and the machinery of the mitochondrial compartments. VDACs are now increasingly recognized as regulatory hubs of the cell. Not surprisingly, even the transient misregulation of VDACs results directly in mitochondrial dysfunction. Additionally, human VDACs are now implicated in interaction with aggregation-prone cytosolic proteins, including Aß, tau, and α-synuclein, contributing directly to the onset of Alzheimer's and Parkinson's diseases. Deducing the interaction dynamics and mechanisms can lead to VDAC-targeted peptide-based therapeutics that can alleviate neurodegenerative states. This review succinctly presents the latest findings of the VDAC interactome, and the mode(s) of VDAC-dependent regulation of biochemical physiology. We also discuss the relevance of VDACs in pathophysiological states and aggregation-associated diseases and address how VDACs will facilitate the development of next-generation precision medicines.


Asunto(s)
Enfermedades Neurodegenerativas , Canales Aniónicos Dependientes del Voltaje , Humanos , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Isoformas de Proteínas/metabolismo , Canales Aniónicos Dependientes del Voltaje/metabolismo
16.
Nat Commun ; 12(1): 5330, 2021 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-34504093

RESUMEN

Most autosomal genes are thought to be expressed from both alleles, with some notable exceptions, including imprinted genes and genes showing random monoallelic expression (RME). The extent and nature of RME has been the subject of debate. Here we investigate the expression of several candidate RME genes in F1 hybrid mouse cells before and after differentiation, to define how they become persistently, monoallelically expressed. Clonal monoallelic expression is not present in embryonic stem cells, but we observe high frequencies of monoallelism in neuronal progenitor cells by assessing expression status in more than 200 clones. We uncover unforeseen modes of allelic expression that appear to be gene-specific and epigenetically regulated. This non-canonical allelic regulation has important implications for development and disease, including autosomal dominant disorders and opens up therapeutic perspectives.


Asunto(s)
Alelos , Desequilibrio Alélico , Epigénesis Genética , Enfermedades Musculares/genética , Células-Madre Neurales/metabolismo , Enfermedades Neurodegenerativas/genética , Ácido Anhídrido Hidrolasas/genética , Ácido Anhídrido Hidrolasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Diferenciación Celular , Quimera , Células Clonales , Metilación de ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Femenino , Dosificación de Gen , Frecuencia de los Genes , Sitios Genéticos , Impresión Genómica , Masculino , Ratones , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Células-Madre Neurales/patología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Osteoporosis/genética , Osteoporosis/metabolismo , Osteoporosis/patología , Receptores de Ácido Kaínico/genética , Receptores de Ácido Kaínico/metabolismo
17.
Sci Rep ; 11(1): 17914, 2021 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-34504131

RESUMEN

Aging, a critical risk factor of several diseases, including neurodegenerative disorders, affects an ever-growing number of people. Cacao supplementation has been suggested to improve age-related neuronal deficits. Therefore, this study investigated the protective effects of raw cacao powder on oxidative stress-induced aging. Male Sprague-Dawley rats were divided into 4 groups: Control (C), D-galactose-induced aging (G), D-galactose injection with 10% (LC), and 16% (HC) cacao powder mixed diet. D-galactose (300 mg/3 mL/kg) was intraperitoneally injected into all but the control group for 12 weeks. Cacao supplemented diets were provided for 8 weeks. The levels of serum Malondialdehyde (MDA), Advanced Glycation End-products (AGEs), brain and liver MDA, the indicators of the D-galactose induced oxidative stress were significantly decreased in LC and HC but increased in G. The Acetylcholinesterase (AChE) activity of brain showed that the cholinergic impairment was significantly lower in LC, and HC than G. Furthermore, the expression levels of catalase (CAT), phospho-Akt/Akt, and procaspase-3 were significantly increased in LC and HC. In conclusion, cacao consumption attenuated the effects of oxidative stress, cholinergic impairment and apoptosis, indicating its potential in future clinical studies.


Asunto(s)
Envejecimiento , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Cacao/química , Suplementos Dietéticos/análisis , Estrés Oxidativo/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Masculino , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Ratas , Ratas Sprague-Dawley
18.
Adv Exp Med Biol ; 1325: 137-149, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34495533

RESUMEN

Extracellular vesicles (EVs), a generic term for any vesicles or particles that are released from cells, play an important role in modulating numerous biological and pathological events, including development, differentiation, aging, thrombus formation, immune responses, neurodegenerative diseases, and tumor progression. During the biogenesis of EVs, they encapsulate biologically active macromolecules (i.e., nucleotides and proteins) and transmit signals for delivering them to neighboring or cells that are located some distance away. In contrast, there are receptor molecules on the surface of EVs that function to mediate EV-to-cell and EV-to-matrix interactions. A growing body of evidence indicates that the EV surface is heavily modified with glycans, the function of which is to regulate the biogenesis and extracellular behaviors of EVs. In this chapter, we introduce the current status of our knowledge concerning EV glycosylation and discuss how it influences EV biology, highlighting the potential roles of EV glycans in clinical applications.


Asunto(s)
Exosomas , Vesículas Extracelulares , Enfermedades Neurodegenerativas , Exosomas/metabolismo , Vesículas Extracelulares/metabolismo , Glicosilación , Humanos , Enfermedades Neurodegenerativas/metabolismo
19.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-34548404

RESUMEN

Homozygous mutation of the RNA kinase CLP1 (cleavage factor polyribonucleotide kinase subunit 1) causes pontocerebellar hypoplasia type 10 (PCH10), a pediatric neurodegenerative disease. CLP1 is associated with the transfer RNA (tRNA) splicing endonuclease complex and the cleavage and polyadenylation machinery, but its function remains unclear. We generated two mouse models of PCH10: one homozygous for the disease-associated Clp1 mutation, R140H, and one heterozygous for this mutation and a null allele. Both models exhibit loss of lower motor neurons and neurons of the deep cerebellar nuclei. To explore whether Clp1 mutation impacts tRNA splicing, we profiled the products of intron-containing tRNA genes. While mature tRNAs were expressed at normal levels in mutant mice, numerous other products of intron-containing tRNA genes were dysregulated, with pre-tRNAs, introns, and certain tRNA fragments up-regulated, and other fragments down-regulated. However, the spatiotemporal patterns of dysregulation do not correlate with pathogenicity for most altered tRNA products. To elucidate the effect of Clp1 mutation on precursor messenger RNA (pre-mRNA) cleavage, we analyzed poly(A) site (PAS) usage and gene expression in Clp1 R140H/- spinal cord. PAS usage was shifted from proximal to distal sites in the mutant mouse, particularly in short and closely spaced genes. Many such genes were also expressed at lower levels in the Clp1 R140H/- mouse, possibly as a result of impaired transcript maturation. These findings are consistent with the hypothesis that select genes are particularly dependent upon CLP1 for proper pre-mRNA cleavage, suggesting that impaired mRNA 3' processing may contribute to pathogenesis in PCH10.


Asunto(s)
Enfermedades Cerebelosas/patología , Enfermedades Neurodegenerativas/patología , Poliadenilación , Procesamiento Postranscripcional del ARN , ARN Mensajero/metabolismo , ARN de Transferencia/metabolismo , Proteínas de Unión al ARN/fisiología , Factores de Transcripción/fisiología , Animales , Enfermedades Cerebelosas/genética , Enfermedades Cerebelosas/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Precursores del ARN/genética , Precursores del ARN/metabolismo , ARN Mensajero/genética , ARN de Transferencia/genética
20.
Int J Mol Sci ; 22(18)2021 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-34576251

RESUMEN

Vitamin E is often associated with health benefits, such as antioxidant, anti-inflammatory and cholesterol-lowering effects. These properties make its supplementation a suitable therapeutic approach in neurodegenerative disorders, for example, Alzheimer's or Parkinson's disease. However, trials evaluating the effects of vitamin E supplementation are inconsistent. In randomized controlled trials, the observed associations often cannot be substantiated. This could be due to the wide variety of study designs regarding the dosage and duration of vitamin E supplementation. Furthermore, genetic variants can influence vitamin E uptake and/or metabolism, thereby distorting its overall effect. Recent studies also show adverse effects of vitamin E supplementation regarding Alzheimer's disease due to the increased synthesis of amyloid ß. These diverse effects may underline the inhomogeneous outcomes associated with its supplementation and argue for a more thoughtful usage of vitamin E. Specifically, the genetic and nutritional profile should be taken into consideration to identify suitable candidates who will benefit from supplementation. In this review, we will provide an overview of the current knowledge of vitamin E supplementation in neurodegenerative disease and give an outlook on individualized, sustainable neuro-nutrition, with a focus on vitamin E supplementation.


Asunto(s)
Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Ciencias de la Nutrición , Estado Nutricional , Vitamina E/química , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/química , Animales , Antiinflamatorios/farmacología , Antioxidantes , Colesterol/química , Suplementos Dietéticos , Variación Genética , Humanos , Ratones , Ratas
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