RESUMEN
This preface introduces the Journal of Neurochemistry Special Issue on Brain Proteostasis. Adequate control of protein homeostasis, or proteostasis, has been at the center stage of brain physiology, and its deregulation may contribute to brain diseases, including several neuropsychiatric and neurodegenerative conditions. Therefore, delineating the processes underlying protein synthesis, folding, stability, function, and degradation in brain cells is key to promoting brain function and identifying effective therapeutic options for neurological disorders. This special issue comprises four review articles and four original articles covering the roles of protein homeostasis in several mechanisms that are of relevance to sleep, depression, stroke, dementia, and COVID-19. Thus, these articles highlight different aspects of proteostasis regulation in the brain and present important evidence on this growing and exciting field.
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COVID-19 , Enfermedades Neurodegenerativas , Deficiencias en la Proteostasis , Humanos , Proteostasis/fisiología , Enfermedades Neurodegenerativas/metabolismo , Encéfalo/metabolismoRESUMEN
Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.
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Autoantígenos/uso terapéutico , Autoinmunidad/inmunología , Factores Inmunológicos/uso terapéutico , Regeneración Nerviosa/inmunología , Enfermedades Neurodegenerativas/terapia , Neuroprotección/inmunología , Péptidos/uso terapéutico , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/terapia , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/terapia , Animales , Acetato de Glatiramer/uso terapéutico , Humanos , Inmunización Pasiva , Inmunomodulación , Proteína Básica de Mielina/uso terapéutico , Enfermedades Neurodegenerativas/inmunología , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/terapia , Fragmentos de Péptidos/uso terapéutico , Deficiencias en la Proteostasis , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/terapia , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/terapiaRESUMEN
EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.
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Proteínas de Unión al Calcio/genética , Trastornos Congénitos de Glicosilación/genética , Retículo Endoplásmico/genética , alfa-Manosidasa/genética , Adolescente , Alelos , Proteínas de Unión al Calcio/deficiencia , Línea Celular , Niño , Preescolar , Trastornos Congénitos de Glicosilación/sangre , Discapacidades del Desarrollo/genética , Femenino , Glicoproteínas/sangre , Glicosilación , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Mutación , Linaje , Polisacáridos/sangre , Deficiencias en la Proteostasis/genética , alfa-Manosidasa/deficienciaRESUMEN
An extensive catalog of plasma membrane (PM) protein mutations related to phenotypic diseases is associated with incorrect protein folding and/or localization. These impairments, in addition to dysfunction, frequently promote protein aggregation, which can be detrimental to cells. Here, we review PM protein processing, from protein synthesis in the endoplasmic reticulum to delivery to the PM, stressing the main repercussions of processing failures and their physiological consequences in pathologies, and we summarize the recent proposed therapeutic strategies to rescue misassembled proteins through different types of chaperones and/or small molecule drugs that safeguard protein quality control and regulate proteostasis.
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Canalopatías/metabolismo , Proteínas de la Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Pliegue de Proteína , Deficiencias en la Proteostasis/metabolismo , Animales , Canalopatías/tratamiento farmacológico , Canalopatías/genética , Humanos , Proteínas de la Membrana/química , Transporte de Proteínas , Deficiencias en la Proteostasis/tratamiento farmacológico , Deficiencias en la Proteostasis/genéticaRESUMEN
Protein misfolding diseases are usually associated with deposits of single "key" proteins that somehow drive the pathology; ß-amyloid and hyperphosphorylated tau accumulate in Alzheimer's disease, α-synuclein in Parkinson's disease, or abnormal prion protein (PrPTSE) in transmissible spongiform encephalopathies (TSEs or prion diseases). However, in some diseases more than two proteins accumulate in the same brain. These diseases might be considered "complex" proteinopathies. We have studied models of TSEs (to explore deposits of PrPTSE and of "secondary proteins") infecting different strains and doses of TSE agent, factors that control incubation period, duration of illness and histopathology. Model TSEs allowed us to investigate whether different features of histopathology are independent of PrPTSE or appear as a secondary result of PrPTSE. Better understanding the complex proteinopathies may help to explain the wide spectrum of degenerative diseases and why some overlap clinically and histopathologically. These studies might also improve diagnosis and eventually even suggest new treatments for human neurodegenerative diseases.
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Enfermedades Neurodegenerativas/fisiopatología , Enfermedades por Prión/fisiopatología , Animales , Modelos Animales de Enfermedad , Humanos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades por Prión/metabolismo , Deficiencias en la Proteostasis/metabolismo , Deficiencias en la Proteostasis/fisiopatologíaRESUMEN
ABSTRACT Protein misfolding diseases are usually associated with deposits of single "key" proteins that somehow drive the pathology; β-amyloid and hyperphosphorylated tau accumulate in Alzheimer's disease, α-synuclein in Parkinson's disease, or abnormal prion protein (PrPTSE) in transmissible spongiform encephalopathies (TSEs or prion diseases). However, in some diseases more than two proteins accumulate in the same brain. These diseases might be considered "complex" proteinopathies. We have studied models of TSEs (to explore deposits of PrPTSE and of "secondary proteins") infecting different strains and doses of TSE agent, factors that control incubation period, duration of illness and histopathology. Model TSEs allowed us to investigate whether different features of histopathology are independent of PrPTSE or appear as a secondary result of PrPTSE. Better understanding the complex proteinopathies may help to explain the wide spectrum of degenerative diseases and why some overlap clinically and histopathologically. These studies might also improve diagnosis and eventually even suggest new treatments for human neurodegenerative diseases.
RESUMEN La acumulación de proteínas con conformación anormal es observada en numerosas enfermedades degenerativas del sistema nervioso. Tales enfermedades están generalmente asociadas con el depósito de una proteína que es importante para la patogenia de la enfermedad; amiloide-β e hiperfosforilación de tau en la Enfermedad de Alzheimer, α-sinucleína en la Enfermedad de Parkinson, y acúmulo de proteína prion anormal (PrPTSE) en las encefalopatías espongiformes transmisibles (EET). Sin embargo, en algunas enfermedades más de dos proteínas se acumulan en el sistema nervioso central. Estas enfermedades pueden considerarse "proteinopatías complejas". Hemos estudiado varios modelos de EET para analizar los depósitos de PrPTSE y la posible acumulación de otras proteínas (que podríamos llamar "proteínas secundarias"). La relación entre proteínas mal plegadas y neurodegeneración no es claro. La mayor parte de las enfermedades neurodegenerativas evolucionan por décadas; por lo tanto los acúmulos proteicos podrían generar diferentes efectos patogénicos en los diferentes estadios de la enfermedad. Alternativamente los acúmulos proteicos podrían ser el resultado de alteraciones del sistema nervioso y no su causa. Dado que la etiología de las ETT es relativamente bien conocido y es atribuido a infección por agentes autoreplicantes que generan malformacion de la proteína prion normal (la isoforma patologica, PrPTSE, propuesta como el agente infeccioso) hemos estudiado varios modelos animales, cepas de agente infectante y dosis del agente causal de ETT. Estos factores controlan el período de incubación, duración de la enfermedad e histopatología. Los modelos animales estudiados nos han permitido investigar si las diferentes características histopatológicas son independientes de PrPTSE o podrían ser secundarias a la acumulación de la misma. Un mejor conocimiento de las proteinopatías complejas podría ayudar a analizar el espectro de enfermedades degenerativas y a su vez, investigar el motivo de la superposición clínico-patológico en algunas de ellas. Estos estudios podrían ayudar en el diagnóstico y eventualmente sugerir nuevas posibles terapéuticas para las enfermedades neurodegenerativas humanas.
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Humanos , Animales , Enfermedades por Prión/fisiopatología , Enfermedades Neurodegenerativas/fisiopatología , Enfermedades por Prión/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Modelos Animales de Enfermedad , Deficiencias en la Proteostasis/fisiopatología , Deficiencias en la Proteostasis/metabolismoRESUMEN
The type II chaperonin CCT is involved in the prevention of the pathogenesis of numerous human misfolding disorders, as it sequesters misfolded proteins, blocks their aggregation and helps them to achieve their native state. In addition, it has been reported that CCT can prevent the toxicity of non-client amyloidogenic proteins by the induction of non-toxic aggregates, leading to new insight in chaperonin function as an aggregate remodeling factor. Here we add experimental evidence to this alternative mechanism by which CCT actively promotes the formation of conformationally different aggregates of γ-tubulin, a non-amyloidogenic CCT client protein, which are mediated by specific CCT-γ-tubulin interactions. The in vitro-induced aggregates were in some cases long fiber polymers, which compete with the amorphous aggregates. Direct injection of unfolded purified γ-tubulin into single-cell zebra fish embryos allowed us to relate this in vitro activity with the in vivo formation of intracellular aggregates. Injection of a CCT-binding deficient γ-tubulin mutant dramatically diminished the size of the intracellular aggregates, increasing the toxicity of the misfolded protein. These results point to CCT having a role in the remodeling of aggregates, constituting one of its many functions in cellular proteostasis.
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Chaperonina con TCP-1 , Agregación Patológica de Proteínas , Desplegamiento Proteico , Deficiencias en la Proteostasis , Tubulina (Proteína) , Animales , Chaperonina con TCP-1/química , Chaperonina con TCP-1/genética , Chaperonina con TCP-1/metabolismo , Humanos , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/metabolismo , Deficiencias en la Proteostasis/genética , Deficiencias en la Proteostasis/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Pez Cebra/metabolismoRESUMEN
The accumulation of protein aggregates has a fundamental role in the patophysiology of distinct neurodegenerative diseases. This phenomenon may have a common origin, where disruption of intracellular mechanisms related to protein homeostasis (here termed proteostasis) control during aging may result in abnormal protein aggregation. The unfolded protein response (UPR) embodies a major element of the proteostasis network triggered by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as possible mechanism of neurodegenerative and synaptic dysfunction, and in addition contribute to the abnormal aggregation of key disease-related proteins. In this article we overview the most recent findings suggesting a causal role of ER stress in neurodegenerative diseases.
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Estrés del Retículo Endoplásmico/fisiología , Enfermedades Neurodegenerativas/etiología , Enfermedad de Alzheimer/etiología , Esclerosis Amiotrófica Lateral/etiología , Animales , Humanos , Enfermedad de Huntington/etiología , Enfermedad de Parkinson/etiología , Deficiencias en la Proteostasis/etiologíaRESUMEN
Cardiovascular disease, which today represents the main cause of death worldwide, is a likely candidate for the application of nanotechnology in the near future. Nanocarriers are currently being developed to deliver medicine (smart drugs) to selected targets in cells and tissues of blood vessels and the heart, as well as to aid in diagnosis and screening for early detection and individualized treatment. Other applications of nanotechnology hold promise for the long run, such as using nanodevices for drug delivery or correcting the misfolding of proteins. With super-potent effects, nanoparticles should be able to evoke therapeutic effects at a lower dose and for longer periods. The development of nanodevices and nanocarriers must take an integral approach that considers many properties-physical, chemical, biological, biochemical, anatomical, morphological, physiological, pharmacological, toxicological, mechanical, electrical, magnetic, thermodynamic, and optical-in order to evaluate biocompatibility and therefore avoid toxicological and/or other adverse effects. Intensified research in relation to nanocarriers and other nanotechnology could help reduce morbidity and mortality in cardiovascular disease.
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Enfermedades Cardiovasculares/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Nanopartículas , Animales , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/química , Diseño de Fármacos , Humanos , Nanotecnología/métodos , Deficiencias en la Proteostasis/tratamiento farmacológico , Factores de Tiempo , Distribución TisularRESUMEN
Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.
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Envejecimiento/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Enfermedades Neurodegenerativas/prevención & control , Sustancias Protectoras/farmacología , Deficiencias en la Proteostasis/prevención & control , Respuesta de Proteína Desplegada/efectos de los fármacos , Adenina/análogos & derivados , Adenina/farmacología , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Caenorhabditis elegans/metabolismo , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Estrés del Retículo Endoplásmico/genética , Guanabenzo/farmacología , Humanos , Indoles/farmacología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Proteoma/genética , Proteoma/metabolismo , Proteostasis/efectos de los fármacos , Deficiencias en la Proteostasis/metabolismo , Deficiencias en la Proteostasis/patología , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismoRESUMEN
Chronic myeloid leukemia (CML) is a myeloproliferative disease with a characteristic BCR-ABL tyrosine kinase (TK) fusion protein. Despite the clinical efficacy accomplished by TKIs therapies, disease progression may affect patient response rate to these inhibitors due to a multitude of factors that could lead to development of a mechanism known as multidrug resistance (MDR). 7-Ketocholesterol (7KC) is an oxidized cholesterol derivative that has been extensively reported to cause cell death in a variety of cancer models. In this study, we showed the in vitro efficacy of 7KC against MDR leukemia cell line, Lucena. 7KC treatment induced reduction in cell viability, together with apoptosis-mediated cell death. Moreover, downregulation of MDR protein caused intracellular drug accumulation and 7KC co-incubation with either Daunorubicin or Vincristine reduced cell viability compared to the use of each drug alone. Additionally, quantitative label-free mass spectrometry-based protein quantification showed alteration of different molecular pathways involved in cell cycle arrest, induction of apoptosis and misfolded protein response. Conclusively, this study highlights the effect of 7KC as a sensitizing agent of multidrug resistance CML and elucidates its molecular mechanisms. SIGNIFICANCE: CML patients treated with tyrosine kinase inhibitors (TKIs) have showed a 5-year estimated overall survival of 89%, with cumulative complete cytogenetic response of 87%. However, development of drug resistance is a common feature of the disease progression. This study aimed at showing the effect of 7KC as a cytotoxic and sensitizing agent of multidrug resistance CML cell lines. The cellular and molecular basis of this compound were elucidated using a comprehensive strategy based on quantitative proteomic and cell biology assays. We showed that 7KC induced cell death and overcomes drug resistance in CML through mechanisms that go beyond the classical MDR1 pathways.
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Resistencia a Antineoplásicos/efectos de los fármacos , Cetocolesteroles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Daunorrubicina/uso terapéutico , Sinergismo Farmacológico , Humanos , Cetocolesteroles/uso terapéutico , Proteómica/métodos , Deficiencias en la Proteostasis/metabolismo , Vincristina/uso terapéuticoRESUMEN
Although new candidate genes for Autism Spectrum Disorder (ASD), Schizophrenia (SCZ), Attention-Deficit/Hyperactivity Disorder (ADHD), and Bipolar Disorder (BD) emerged from genome-wide association studies (GWAS), their underlying molecular mechanisms remain poorly understood. Evidences of the involvement of intrinsically disordered proteins in diseases have grown in the last decade. These proteins lack tridimensional structure under physiological conditions and are involved in important cellular functions such as signaling, recognition and regulation. The aim of the present study was to identify the role and abundance of intrinsically disordered proteins in a set of psychiatric diseases and to test whether diseases are different regarding protein intrinsic disorder. Our hypothesis is that differences across psychiatric illnesses phenotypes and symptoms may arise from differences in intrinsic protein disorder content and properties of each group. A bioinformatics prediction of intrinsic disorder was performed in proteins retrieved based on top findings from GWAS, Copy Number Variation and candidate gene investigations for each disease. This approach revealed that about 80% of studied proteins presented long stretches of disorder. This amount was significantly higher than that observed in general eukaryotic proteins, and those involved in cardiovascular diseases. These results suggest that proteins with intrinsic disorder are a common feature of neurodevelopment and synaptic transmission processes which are potentially involved in the etiology of psychiatric diseases. Moreover, we identified differences between ADHD and ASD when the binary prediction of structure and putative binding sites were compared. These differences may be related to variation in symptom complexity between both diseases. © 2016 Wiley Periodicals, Inc.
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Trastornos Mentales/genética , Trastornos Mentales/fisiopatología , Deficiencias en la Proteostasis/genética , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno del Espectro Autista/genética , Trastorno Bipolar/genética , Variaciones en el Número de Copia de ADN , Bases de Datos de Ácidos Nucleicos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Trastornos Mentales/metabolismo , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genéticaRESUMEN
Pharmacoperones are hydrophobic molecule drugs that enter cells and serve as a molecular framework to cause misfolded mutant proteins to fold properly and adopt a stable conformation compatible with proper intracellular trafficking. Pharmacoperones have successfully been used experimentally to rescue function of some misfolded proteins (enzymes, receptors, channels) that lead to disease. Identification of pharmacoperones by high-throughput screens of drug libraries will likely provide new molecules that may be potentially useful to treat diseases caused by protein misfolding.
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Chaperonas Moleculares/metabolismo , Proteínas/metabolismo , Deficiencias en la Proteostasis/tratamiento farmacológico , Animales , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Chaperonas Moleculares/química , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Pliegue de Proteína , Proteínas/química , Deficiencias en la Proteostasis/patologíaRESUMEN
Misfolding and aggregation of proteins are the main features of a group of diseases termed Protein Misfolding Disorders (PMDs). PMDs include Alzheimer's disease and Transmissible Spongiform Encephalopathies, among many others. The deposition of protein aggregates is the main responsible for tissue damage and the consequent clinical signs generated in such disorders. In this review, we will focus in the role of protein aggregates in these diseases and in the putative mechanisms by which they exert their toxicity.
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Enfermedades Neurodegenerativas , Deficiencias en la Proteostasis , Humanos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Deficiencias en la Proteostasis/genética , Deficiencias en la Proteostasis/metabolismo , Deficiencias en la Proteostasis/fisiopatologíaAsunto(s)
Deficiencias en la Proteostasis , Deficiencia de alfa 1-Antitripsina , Animales , Caenorhabditis elegans , Modelos Animales de Enfermedad , Humanos , Deficiencias en la Proteostasis/complicaciones , Deficiencias en la Proteostasis/terapia , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/terapiaRESUMEN
Misfolding and aggregation of proteins are the main features of a group of diseases termed Protein Misfolding Disorders (PMDs). PMDs include Alzheimer's disease and Transmissible Spongiform Encephalopathies, among many others. The deposition of protein aggregates is the main responsible for tissue damage and the consequent clinical signs generated in such disorders. In this review, we will focus in the role of protein aggregates in these diseases and in the putative mechanisms by which they exert their toxicity.
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Humanos , Enfermedades Neurodegenerativas , Deficiencias en la Proteostasis , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Deficiencias en la Proteostasis/genética , Deficiencias en la Proteostasis/metabolismo , Deficiencias en la Proteostasis/fisiopatologíaRESUMEN
The misfolding of proteins into a toxic conformation is proposed to be at the molecular foundation of a number of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Evidence that α-synuclein amyloidogenesis plays a causative role in the development of Parkinson's disease is furnished by a variety of genetic, neuropathological and biochemical studies. There is a major interest in understanding the structural and toxicity features of the various species populated along the aggregation pathway of this protein. The development of multidimensional nuclear magnetic resonance (NMR) spectroscopy in liquid and solid state over the last decade has significantly increased the scope of molecules that are amenable for structural studies. The aim of this review is to provide a picture of how NMR tools were used in concert to decipher the structural and dynamic properties of the intrinsically disordered protein α-synuclein in its native, oligomeric, fibril and membrane-bound states. Understanding the structural and molecular basis behind the aggregation pathway of α-synuclein is key to advance in the design of a therapeutic strategy.
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Amiloide , Espectroscopía de Resonancia Magnética , alfa-Sinucleína/química , Secuencia de Aminoácidos , Amiloide/química , Humanos , Datos de Secuencia Molecular , Enfermedad de Parkinson/fisiopatología , Pliegue de Proteína , Deficiencias en la Proteostasis/fisiopatología , Alineación de SecuenciaRESUMEN
Even though our knowledge of how proteins misfold and aggregate is deeper nowadays, the mechanisms driving this process are still poorly understood. Among the factors involved, membranes should be taken into account. Indeed, convincing evidence suggests that membranes may influence protein folding, misfolding and aggregation. In fact, membrane lipid composition of different cellular types may attenuate or intensify the environmental pressure over protein folding equilibrium. In the present review the aim is to make an up-to-date analysis of the membrane influence on protein aggregation from a biophysical point of view in order to provide useful tools for researchers from other fields. In particular, we discuss how membranes can alter protein environment, e.g. increasing local protein concentration, lowering pH and dielectric constant, allowing accessibility to the hydrophobic milieu and promoting surface crowding, all of which will lead to protein aggregation. In addition, we review the role that specific lipids may exert on protein aggregation and finally we analyse the possible implication of membrane-related oxidative stress on amyloidogenesis.
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Amiloide/metabolismo , Membrana Celular/fisiología , Modelos Biológicos , Biofisica , Membrana Celular/patología , Humanos , Estrés Oxidativo , Deficiencias en la Proteostasis/fisiopatología , TermodinámicaRESUMEN
Cells require a protein quality control (PQC) system to obtain a correct balance between folding and the degradation of incorrectly folded or misfolded proteins. This system maintains protein homeostasis and is essential for life. Key components of the PQC are molecular chaperones, which compose a ubiquitous class of proteins that mediate protein quality control by aiding in both the correct folding of proteins and the elimination of proteins that are misfolded due to cellular stress or mutation. Recent studies showed that protein homeostasis has an important role in nutrition and aging, increasing the relevance of the heat shock response to human health. This review summarizes our current knowledge of the molecular chaperone system and its role in protein homeostasis.