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We identified a sub-group (25%) of people with schizophrenia (muscarinic receptor deficit schizophrenia (MRDS)) that are characterised because of markedly lower levels of cortical muscarinic M1 receptors (CHRM1) compared to most people with the disorder (non-MRDS). Notably, bioinformatic analyses of our cortical gene expression data shows a disturbance in the homeostasis of a biochemical pathway that regulates levels of CHRM1. A step in this pathway is the processing of ß-amyloid precursor protein (APP) and therefore we postulated there would be altered levels of APP in the frontal cortex from people with MRDS. Here we measure levels of CHRM1 using [3H]pirenzepine binding, soluble APP (sAPP) using Western blotting and amyloid beta peptides (Aß1-40 and Aß1-42) using ELISA in the frontal cortex (Brodmann's area 6: BA 6; MRDS = 14, non-MRDS = 14, controls = 14). We confirmed the MRDS cohort in this study had the expected low levels of [3H]pirenzepine binding. In addition, we showed that people with schizophrenia, independent of their sub-group status, had lower levels of sAPP compared to controls but did not have altered levels of Aß1-40 or Aß1-42. In conclusion, whilst changes in sAPP are not restricted to MRDS our data could indicate a role of APP, which is important in axonal and synaptic pruning, in the molecular pathology of the syndrome of schizophrenia.
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Precursor de Proteína beta-Amiloide , Esquizofrenia , Humanos , Precursor de Proteína beta-Amiloide/metabolismo , Pirenzepina/metabolismo , Péptidos beta-Amiloides , Esquizofrenia/genética , Lóbulo Frontal/metabolismo , Receptor Muscarínico M1/genéticaRESUMEN
Drug discovery and clinical trial design for dementia have historically been challenging. In part these challenges have arisen from patient heterogeneity, length of disease course, and the tractability of a target for the brain. Applying big data analytics and machine learning tools for drug discovery and utilizing them to inform successful clinical trial design has the potential to accelerate progress. Opportunities arise at multiple stages in the therapy pipeline and the growing availability of large medical data sets opens possibilities for big data analyses to answer key questions in clinical and therapeutic challenges. However, before this goal is reached, several challenges need to be overcome and only a multi-disciplinary approach can promote data-driven decision-making to its full potential. Herein we review the current state of machine learning applications to clinical trial design and drug discovery, while presenting opportunities and recommendations that can break down the barriers to implementation.
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Inteligencia Artificial , Demencia , Humanos , Descubrimiento de Drogas , Aprendizaje Automático , Progresión de la Enfermedad , Demencia/tratamiento farmacológicoRESUMEN
Ferroptosis, an iron-dependent regulated cell death triggered by high lipid peroxide levels, has been implicated in several neurodegenerative diseases, including Parkinson's disease (PD). Brain regions such as the striatum are highly rich in both peroxidation susceptible PUFAs and iron, which accumulate at a greater rate than age in PD. The exact molecular pathways and patho-physiological conditions promoting cell death in the dopaminergic neurons that are particularly susceptible in PD remain elusive. In the current work, we show that modifying the PUFA composition in membranes of dopaminergic neurons using arachidonic acid (AA) can determine ferroptosis susceptibility. Furthermore, cotreatment with iron (Fe), increases AA-containing phospholipid association and synergistically promotes high lipid peroxidation to facilitate ferroptosis. Ex vivo analysis with organotypic brain slices, confirm that AA + Fe induces cell death in the nigrostriatal pathway and can be rescued by the anti-ferroptotic drug Ferrostatin-1. Prevention of ferroptotic AA + Fe induced cell death through inhibition of ACSL4, ALOX15 or ALOX15B provides mechanistic support of this lipid peroxidation pathway being involved in dopaminergic neuronal death and novel potential pharmacological targets for neuroprotective strategies in PD.
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Araquidonato 15-Lipooxigenasa , Coenzima A Ligasas , Ferroptosis , Hierro , Neuronas Dopaminérgicas/metabolismo , Hierro/metabolismo , Peroxidación de Lípido , Araquidonato 15-Lipooxigenasa/metabolismo , Coenzima A Ligasas/metabolismoRESUMEN
The accumulation of toxic protein aggregates in multiple neurodegenerative diseases is associated with defects in the macroautophagy/autophagy-lysosome pathway. The amelioration of disease phenotypes across multiple models of neurodegeneration can be achieved through modulating the master regulator of lysosome function, TFEB (transcription factor EB). Using a novel multi-parameter high-throughput screen for cytoplasmic:nuclear translocation of endogenous TFEB and the related transcription factor TFE3, we screened the Published Kinase Inhibitor Set 2 (PKIS2) library as proof of principle and to identify kinase regulators of TFEB and TFE3. Given that TFEB and TFE3 are responsive to cellular stress we have established assays for cellular toxicity and lysosomal function, critical to ensuring the identification of hit compounds with only positive effects on lysosome activity. In addition to AKT inhibitors which regulate TFEB localization, we identified a series of quinazoline-derivative compounds that induced TFEB and TFE3 translocation. A novel series of structurally-related analogs was developed, and several compounds induced TFEB and TFE3 translocation at higher potency than previously screened compounds. KINOMEscan and cell-based KiNativ kinase profiling revealed high binding for the PRKD (protein kinase D) family of kinases, suggesting good selectivity for these compounds. We describe and utilize a cellular target-validation platform using CRISPRi knockdown and orthogonal PRKD inhibitors to demonstrate that the activity of these compounds is independent of PRKD inhibition. The more potent analogs induced subsequent upregulation of the CLEAR gene network and cleared pathological HTT protein in a cellular model of proteinopathy, demonstrating their potential to alleviate neurodegeneration-relevant phenotypes. Abbreviations: AD: Alzheimer disease; AK: adenylate kinase; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; HD: Huntington disease; PD: Parkinson disease; PKIS2: Published Kinase Inhibitor Set 2; PRKD: protein kinase D; TFEB: transcription factor EB.
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Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Autofagia/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Regulación de la Expresión Génica , Núcleo Celular/metabolismo , Lisosomas/metabolismoRESUMEN
There is a continued unmet need for treatments that can slow Parkinson's disease progression due to the lack of understanding behind the molecular mechanisms underlying neurodegeneration. Since its discovery, ferroptosis has been implicated in several diseases and represents a therapeutic target in Parkinson's disease. Here, we use two highly relevant human dopaminergic neuronal models to show that endogenous levels of α-synuclein can determine the sensitivity of dopaminergic neurons to ferroptosis. We show that reducing α-synuclein expression in dopaminergic neurons leads to ferroptosis evasion, while elevated α-synuclein expression in patients' small-molecule-derived neuronal precursor cells with SNCA triplication causes an increased vulnerability to lipid peroxidation and ferroptosis. Lipid profiling reveals that ferroptosis resistance is due to a reduction in ether-linked phospholipids, required for ferroptosis, in neurons depleted of α-synuclein (α-syn). These results provide a molecular mechanism linking α-syn levels to the sensitivity of dopaminergic neurons to ferroptosis, suggesting potential therapeutic relevance.
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Ferroptosis , Enfermedad de Parkinson , Neuronas Dopaminérgicas/metabolismo , Humanos , Enfermedad de Parkinson/metabolismo , Éteres Fosfolípidos/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
Dementia affects millions of individuals worldwide, yet there are no effective treatments. Alzheimer's disease, the most common form of dementia, is characterized by amyloid and tau pathology with amyloid accumulation thought to precipitate tau pathology, neurodegeneration, and dementia. The Religious Orders Study and Memory and Aging Project (ROSMAP) cohort is a unique resource with quantitative pathology from multiple brain regions, RNA sequencing, and longitudinal cognitive data. Our previous work applying machine learning to the RNA sequencing data identified lactoferrin (LTF) as the gene most predictive of amyloid accumulation with a potential amyloidogenic mechanism identified in vitro and with cell-culture models. In the present study, we examined which pathologies and genes were related to cognitive status (dementia, mild impairment, and no cognitive impairment) and rate of cognitive decline. Tau load in the anterior cingulate and ADAMTS2, encoding a metallopeptidase, were the respective regional pathology and gene most associated with cognitive decline, while PRTN3, encoding a serine protease, was the key protective feature. ADAMTS2, but not PRTN3, was related to amyloid and tau load in the previous study while LTF was not related to cognitive decline here. These findings confirm a general relationship between tau pathology and dementia, show the specific importance of tau pathology in the anterior cingulate cortex and identify ADAMTS2 as a potential target for slowing cognitive decline.
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Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunological disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochemical properties of the selective PI5P4Kγ inhibitor, NIH-12848 (1). These improvements enabled the demonstration that this chemotype engages PI5P4Kγ in intact cells and that compounds from this series do not inhibit PI5P4Kα or PI5P4Kß. Furthermore, the first X-ray structure of PI5P4Kγ bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chemical series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 Å from the ATP pocket.
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Adenosina Trifosfato/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Regulación Alostérica/efectos de los fármacos , Unión Competitiva , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Fosfotransferasas (Aceptor de Grupo Alcohol)/química , Especificidad por SustratoRESUMEN
Iron dysregulation, dopamine depletion, cellular oxidative stress and α-synuclein protein mis-folding are key neuronal pathological features seen in the progression of Parkinson's disease. Iron chelators endowed with one or more therapeutic modes of action have long been suggested as disease modifying therapies for its treatment. In this study, novel 1-hydroxypyrazin-2(1H)-one iron chelators were synthesized and their physicochemical properties, iron chelation abilities, antioxidant capacities and neuroprotective effects in a cell culture model of Parkinson's disease were evaluated. Physicochemical properties (log ß, log D7.4, pL0.5) suggest that these ligands have a poorer ability to penetrate cell membranes and form weaker iron complexes than the closely related 1-hydroxypyridin-2(1H)-ones. Despite this, we show that levels of neuroprotection provided by these ligands against the catecholaminergic neurotoxin 6-hydroxydopamine in vitro were comparable to those seen previously with the 1-hydroxypyridin-2(1H)-ones and the clinically used iron chelator Deferiprone, with two of the ligands restoring cell viability to ≥89% compared to controls. Two of the ligands were endowed with additional phenol moieties in an attempt to derive multifunctional chelators with dual iron chelation/antioxidant activity. However, levels of neuroprotection with these ligands were no greater than ligands lacking this moiety, suggesting the neuroprotective properties of these ligands are due primarily to chelation and passivation of intracellular labile iron, preventing the generation of free radicals and reactive oxygen species that otherwise lead to the neuronal cell death seen in Parkinson's disease.
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Enfermedad de ParkinsonRESUMEN
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons leading to death within 3 years and without a curative treatment. Neurotrophic growth factors (NTFs) are pivotal for cell survival. A reason for the lack of patient efficacy with single recombinant NTF brain infusion is likely to be due to the synergistic neuroprotective action of multiple NTFs on a diverse set of signaling pathways. Fractionated (protein size <50, <30, <10, <3 kDa) heat-treated human platelet lysate (HHPL) preparations were adapted for use in brain tissue with the aim of demonstrating therapeutic value in ALS models and further elucidation of the mechanisms of action. In neuronal culture all fractions induced Akt-dependent neuroprotection as well as a strong anti-apoptotic and anti-ferroptotic action. In the <3 kDa fraction anti-ferroptotic properties were shown to be GPX4 dependent highlighting a role for other platelet elements associated with NTFs. In the SOD1G86R mouse model, lifespan was strongly increased by intracerebroventricular delivery of HHPL or by intranasal administration of <3 kDa fraction. Our results suggest that the platelet lysate biomaterials are neuroprotective in ALS. Further studies would now validate theragnostic biomarker on its antiferroptotic action, for further clinical development.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Animales , Materiales Biocompatibles/uso terapéutico , Terapia Biológica , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Neuronas Motoras/metabolismo , Enfermedades Neurodegenerativas/terapia , Neuroprotección , Superóxido Dismutasa/metabolismoRESUMEN
Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-ß peptide (Aß) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection; however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia diverted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal Aß production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aß production, neuroinflammation and iron dysregulation.
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Enfermedad de Alzheimer , Lactoferrina , Proteínas de Fase Aguda , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , HumanosRESUMEN
Glutaminyl cyclases (QC) catalyze the formation of neurotoxic pGlu-modified amyloid-ß peptides found in the brains of people with Alzheimer's disease (AD). Reports of several-fold increases in soluble QC (sQC) expression in the brain and peripheral circulation of AD individuals has prompted the development of QC inhibitors as potential AD therapeutics. There is, however, a lack of standardized quantitative data on QC expression in human tissues, precluding inter-laboratory comparison and validation. We tested the hypothesis that QC is elevated in AD tissues by quantifying levels of sQC protein and activity in post-mortem brain tissues from AD and age-matched control individuals. We found a modest but statistically significant increase in sQC protein, which paralleled a similar increase in enzyme activity. In plasma samples sourced from the Australian Imaging, Biomarker and Lifestyle study we determined that QC activity was not different between the AD and control group, though a modest increase was observed in female AD individuals compared to controls. Plasma QC activity was further correlated with levels of circulating monocytes in AD individuals. These data provide quantitative evidence that alterations in QC expression are associated with AD pathology.
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Enfermedad de Alzheimer/enzimología , Aminoaciltransferasas/metabolismo , Encéfalo/enzimología , Anciano , Anciano de 80 o más Años , Aminoaciltransferasas/antagonistas & inhibidores , Aminoaciltransferasas/sangre , Australia , Autopsia , Biomarcadores , Bases de Datos Factuales , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Valores de Referencia , Caracteres SexualesRESUMEN
Parkinson's Disease (PD) is a common and progressive neurodegenerative disorder characterised by motor impairments as well as non-motor symptoms. While dopamine-based therapies are effective in fighting the symptoms in the early stages of the disease, a lack of neuroprotective drugs means that the disease continues to progress. Along with the traditionally recognised pathological hallmarks of dopaminergic neuronal death and intracellular α-synuclein (α-syn) depositions, iron accumulation, elevated oxidative stress and lipid peroxidation damage are further conspicuous features of PD pathophysiology. However, the underlying mechanisms linking these pathological hallmarks with neurodegeneration still remain unclear. Ferroptosis, a regulated iron dependent cell death pathway involving a lethal accumulation of lipid peroxides, shares several features with PD pathophysiology. Interestingly, α-syn has been functionally linked with the metabolism of both iron and lipid, suggesting a possible interplay between dysregulated α-syn and other PD pathological hallmarks related to ferroptosis. This review will address the importance for understanding these disease mechanisms that could be targeted therapeutically. Anti-ferroptosis molecules are neuroprotective in PD animal models and the anti-ferroptotic iron chelator, deferiprone, slowed disease progression and improved motor function in two independent clinical trials for PD. An ongoing larger multi-centre phase 2 clinical trial will confirm the therapeutic potential of deferiprone and the relevance of ferroptosis in PD. This review addresses the known pathological features of PD in relation to the ferroptosis pathway with therapeutic implications of targeting this cell death pathway.
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Ferroptosis/fisiología , Peroxidación de Lípido/fisiología , Estrés Oxidativo/fisiología , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Ferroptosis/efectos de los fármacos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/patología , alfa-Sinucleína/efectos de los fármacosRESUMEN
Bimolecular fluorescence complementation (BiFC) was introduced a decade ago as a method to monitor alpha-synuclein (α-syn) oligomerization in intact cells. Since then, several α-syn BiFC cellular assays and animal models have been developed based on the assumption that an increase in the fluorescent signal correlates with increased α-syn oligomerization or aggregation. Despite the increasing use of these assays and models in mechanistic studies, target validation and drug screening, there have been no reports that (1) validate the extent to which the BiFC fluorescent signal correlates with α-syn oligomerization at the biochemical level; (2) provide a structural characterization of the oligomers and aggregates formed by the BiFC. To address this knowledge gap, we first analysed the expression level and oligomerization properties of the individual constituents of α-syn-Venus, one of the most commonly used BiFC systems, in HEK-293 & SH-SY5Y cells from three different laboratories using multiple biochemical approaches and techniques. Next, we investigated the biochemical and aggregation properties of α-syn upon co-expression of both BiFC fragments. Our results show that (1) the C-terminal-Venus fused to α-syn (α-syn-Vc) is present in much lower abundance than its counterpart with N-terminal-Venus fused to α-syn (Vn-α-syn); (2) Vn-α-syn exhibits a high propensity to form oligomers and higher-order aggregates; and (3) the expression of either or both fragments does not result in the formation of α-syn fibrils or cellular inclusions. Furthermore, our results suggest that only a small fraction of Vn-α-syn is involved in the formation of the fluorescent BiFC complex and that some of the fluorescent signal may arise from the association or entrapment of α-syn-Vc in Vn-α-syn aggregates. The fact that the N-terminal fragment exists predominantly in an aggregated state also indicates that one must exercise caution when using this system to investigate α-syn oligomerization in cells or in vivo. Altogether, our results suggest that cellular and animal models of oligomerization, aggregation and cell-to-cell transmission based on the α-syn BiFC systems should be thoroughly characterized at the biochemical level to ensure that they reproduce the process of interest and measure what they are intended to measure.
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Imagen Óptica/métodos , Agregación Patológica de Proteínas , alfa-Sinucleína , Animales , Células HEK293 , Humanos , Modelos Animales , Agregado de ProteínasRESUMEN
The proteolytic cleavage of ß-amyloid precursor protein (APP) to form the amyloid beta (Aß) peptide is related to the pathogenesis of Alzheimer's disease (AD) because APP mutations that influence this processing either induce familial AD or mitigate the risk of AD. Yet Aß formation itself may not be pathogenic. APP promotes neuronal iron efflux by stabilizing the cell-surface presentation of ferroportin, the only iron export channel of cells. Mislocalization of APP can promote iron retention, thus we hypothesized that changes in endocytotic trafficking associated with altered APP processing could contribute to the neuronal iron elevation and oxidative burden that feature in AD pathology. Here, we demonstrate, using genetic and pharmacological approaches, that endocytotic amyloidogenic processing of APP impairs iron export by destabilizing ferroportin on the cell surface. Conversely, preferential non-amyloidogenic processing of APP at the cell surface promotes ferroportin stabilization to decrease intraneuronal iron. A new Aß-independent hypothesis emerges where the amyloidogenic processing of APP, combined with age-dependent iron elevation in the tissue, increases pro-oxidant iron burden in AD.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Humanos , Hierro , NeuronasRESUMEN
BACKGROUND: Continuous compensation of dopamine represents an ideal symptomatic treatment for Parkinson's disease (PD). The feasibility in intracerebroventricular administration (i.c.v.) of dopamine previously failed because of unresolved dopamine oxidation. OBJECTIVES: We aim to test the feasibility, safety margins and efficacy of continuous i.c.v. of anaerobic-dopamine (A-dopamine) with a pilot translational study in a non-human primate model of PD. METHODS: Continuous and circadian i.c.v. of A-dopamine was administered through a micro-pump connected to a subcutaneous catheter implanted into the right frontal horn of 8 non-human primates treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). A-dopamine was assessed at acute doses previously reported for dopamine as well as evaluating the long term therapeutic index of A-dopamine in comparison to anaerobically prepared L-dopa or methyl ester L-dopa. RESULTS: Over 60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms (therapeutic index from 30 to 70 mg/day) without tachyphylaxia. No dyskinesia was observed even with very high doses. Death after 1 to 10 days (without neuronal alteration) was only observed with doses in excess of 160 mg whereas L-dopa i.c.v. was not effective at any dose. The technical feasibility of the administration regimen was confirmed for an anaerobic preparation of dopamine and for administration of a minimal infusion volume by micro-pump at a constant flow that prevented obstruction. CONCLUSION: Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.
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Dopamina/administración & dosificación , Infusiones Intraventriculares , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Antiparkinsonianos/farmacología , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/análogos & derivados , Levodopa/farmacología , Macaca , Masculino , Trastornos Parkinsonianos/tratamiento farmacológico , Proyectos PilotoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer's disease, AD), automaticity (Parkinson's disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Terapia por Quelación , Deferiprona/farmacología , Quelantes del Hierro/farmacología , Hierro/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Terapia por Quelación/métodos , Terapia por Quelación/normas , Humanos , Enfermedad de Parkinson/metabolismoRESUMEN
Objectives: The objective of this study was to determine whether a breakdown in proteins regulating cortical iron homeostasis could be involved in the pathophysiology of mood disorders.Methods: Levels of select proteins responsible for cortical iron transport were quantitated by Western blotting of Brodmann's (BA) areas 6 and 10 from patients with major depressive disorder (n = 13), bipolar disorder (n = 12) and age/sex matched controls (n = 13).Results: We found the inactive form of ceruloplasmin was lower in BA 6 from males compared to females. Levels of copper containing ceruloplasmin was lower in BA 6 from suicide completers whilst levels of amyloid precursor protein, TAU and transferrin were higher in BA 10 from those individuals. The level of prion protein was lower in BA 6 from subjects with major depressive disorder.Conclusions: Our data suggests that perturbation in cortical iron transport proteins is not prevalent in mood disorders. By contrast, our data suggests changes in iron transport proteins in BA 6 and BA 10 are present after suicide completion. If these changes were present before death, they could have had a role in the genesis of the contemplation and completion of suicide.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Suicidio , Proteínas Portadoras , Corteza Cerebral , Femenino , Humanos , Hierro/metabolismo , MasculinoRESUMEN
The original version of this article unfortunately contained a mistake in the author name. The family name of Dr. Vanessa A. Johannsen should be written as "Johanssen."
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Extensive loss of dopaminergic neurons and aggregation of the protein α-synuclein into ubiquitin-positive Lewy bodies represents a major neuropathological hallmark of Parkinson's disease (PD). At present, the generation of large nuclear-associated Lewy bodies from endogenous wild-type α-synuclein, translationally regulated under its own promoter in human cell culture models, requires costly and time-consuming protocols. Here, we demonstrate that fully differentiated human SH-SY5Y neuroblastoma cells grown in three-dimensional cell culture develop Lewy-body-like pathology upon exposure to exogenous α-synuclein species. In contrast to most cell- and rodent-based PD models, which exhibit multiple diffuse α-synuclein aggregates throughout the cytoplasm, a single large nuclear inclusion that is immunopositive for α-synuclein and ubiquitin is rapidly obtained in our model. This was achieved without the need for overexpression of α-synuclein or genetic modification of the cell line. However, phosphorylation of α-synuclein within these inclusions was not observed. The system described here provides an ideal tool to screen compounds to therapeutically intervene in Lewy body formation, and to investigate the mechanisms involved in disease progression in synucleinopathies.