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1.
Biochemistry (Mosc) ; 84(10): 1143-1150, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694510

RESUMO

Mitochondria are essential organelles of eukaryotic cell that provide its respiratory function by means of the electron transfer chain. Expression of mitochondrial genes is organized in a bacterial-like manner; however multiple evolutionary differences are observed between the two systems, including translation initiation machinery. This review is dedicated to the mitochondrial translation initiation factor 3 (IF3mt), which plays a key role in the protein synthesis in mitochondria. Involvement of IF3mt in human health and disease is discussed.


Assuntos
Fatores de Iniciação em Eucariotos/química , Fatores de Iniciação em Eucariotos/metabolismo , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Doença de Parkinson/metabolismo , Humanos , Mitocôndrias/metabolismo
2.
Curr Top Med Chem ; 19(25): 2318-2333, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31629395

RESUMO

The enzyme L-DOPA decarboxylase (DDC), also called aromatic-L-amino-acid decarboxylase, catalyzes the biosynthesis of dopamine, serotonin, and trace amines. Its deficiency or perturbations in expression result in severe motor dysfunction or a range of neurodegenerative and psychiatric disorders. A DDC substrate, L-DOPA, combined with an inhibitor of the enzyme is still the most effective treatment for symptoms of Parkinson's disease. In this review, we provide an update regarding the structures, functions, and inhibitors of DDC, particularly with regards to the treatment of Parkinson's disease. This information will provide insight into the pharmacological treatment of Parkinson's disease.


Assuntos
Descarboxilases de Aminoácido-L-Aromático/metabolismo , Inibidores Enzimáticos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/química , Doença de Parkinson/enzimologia , Doença de Parkinson/metabolismo
3.
BMC Bioinformatics ; 20(1): 494, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604427

RESUMO

BACKGROUND: Literature derived knowledge assemblies have been used as an effective way of representing biological phenomenon and understanding disease etiology in systems biology. These include canonical pathway databases such as KEGG, Reactome and WikiPathways and disease specific network inventories such as causal biological networks database, PD map and NeuroMMSig. The represented knowledge in these resources delineates qualitative information focusing mainly on the causal relationships between biological entities. Genes, the major constituents of knowledge representations, tend to express differentially in different conditions such as cell types, brain regions and disease stages. A classical approach of interpreting a knowledge assembly is to explore gene expression patterns of the individual genes. However, an approach that enables quantification of the overall impact of differentially expressed genes in the corresponding network is still lacking. RESULTS: Using the concept of heat diffusion, we have devised an algorithm that is able to calculate the magnitude of regulation of a biological network using expression datasets. We have demonstrated that molecular mechanisms specific to Alzheimer (AD) and Parkinson Disease (PD) regulate with different intensities across spatial and temporal resolutions. Our approach depicts that the mitochondrial dysfunction in PD is severe in cortex and advanced stages of PD patients. Similarly, we have shown that the intensity of aggregation of neurofibrillary tangles (NFTs) in AD increases as the disease progresses. This finding is in concordance with previous studies that explain the burden of NFTs in stages of AD. CONCLUSIONS: This study is one of the first attempts that enable quantification of mechanisms represented as biological networks. We have been able to quantify the magnitude of regulation of a biological network and illustrate that the magnitudes are different across spatial and temporal resolution.


Assuntos
Algoritmos , Encéfalo/metabolismo , Doenças Neurodegenerativas/metabolismo , Biologia de Sistemas/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Regulação da Expressão Gênica , Humanos , Redes e Vias Metabólicas , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Mapas de Interação de Proteínas , Transdução de Sinais
4.
Int J Mol Sci ; 20(18)2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505809

RESUMO

Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer's disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson's disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid ß 42 (Aß42) degradation product Aß38, and this indicator of Aß42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted Aß42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing Aß deposits as well. PADK also reduced amyloidogenic peptides and α-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Lisossomos/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Lisossomos/genética , Lisossomos/patologia , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Sinapses/metabolismo , Sinapses/patologia
5.
Clin Nucl Med ; 44(11): 855-859, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31490312

RESUMO

PURPOSE OF THE REPORT: Oxidative stress is a leading factor in the pathogenesis of idiopathic Parkinson disease (IPD). Two intrinsic antioxidative molecules, bilirubin and uric acid, are known to protect dopaminergic neurons from oxidative stress in IPD. The objective of this study was to determine the relationship between basal serum levels of 2 molecules and dopaminergic deficit assessed by dopamine transporter imaging with F-fluorinated-N-3-fluoropropyl-2-ß-carboxymethoxy-3-ß-(4-iodophenyl)nortropane ([F]FP-CIT) PET/CT in patients with early-stage drug-naive IPD. METHODS: Cases of IPD patients who possess the levels of uric acid and bilirubin within a month from [F]FP-CIT PET/CT from January 2011 to December 2016 were retrospectively reviewed. As a control, the same criteria applied to patients with essential tremor (ET). PET images were analyzed using volume-of-interest templates for 12 striatal subregions and 1 occipital area, and the specific-to-nonspecific binding ratio (SNBR) was calculated. RESULTS: One hundred five patients with drug-naive, early-stage IPD and 62 patients with ET were finally included. Levels of bilirubin were significantly higher in the IPD group than in controls (P = 0.026), and bilirubin level was the factor showing the most correlations with SNBR in IPD (P < 0.001), whereas uric acid showed no such difference or relationship. Furthermore, levels of bilirubin showed a positive correlation with SNBR in more affected posterior putamen in the IPD group (Pearson correlation coefficient, ρ = 0.456; P < 0.001), but a negative one in the ET group (ρ = -0.440, P < 0.001). CONCLUSIONS: Bilirubin, not uric acid, was the most significant antioxidant marker for dopaminergic deficit in early-stage drug-naive IPD assessed by [F]FP-CIT PET/CT.


Assuntos
Bilirrubina/metabolismo , Neostriado/metabolismo , Doença de Parkinson/metabolismo , Tropanos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Adulto Jovem
6.
Mar Drugs ; 17(9)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480724

RESUMO

Mitochondria are considered to be the powerhouses of cells. They are the most commonly damaged organelles within dopaminergic neurons in patients with Parkinson's disease (PD). Despite the importance of protecting neuronal mitochondria in PD patients, the detailed mechanisms underlying mitochondrial dysfunction during pathogenesis and pathophysiological progression of PD have not yet been elucidated. We investigated the protective action of fucoidan against the detrimental action of 1-methyl-4-phenyl-pyridinium (MPP+), a neurotoxin used to model PD, in the mitochondria of SH-SY5Y neural cells. Fucoidan increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and protected the cells from MPP+-induced apoptosis by upregulating the 5' adenosine monophosphate-activated protein kinase (AMPK)-PGC-1α axis. These effects were blocked by the silencing of the PGC-1α axis. These results indicated that fucoidan protects SH-SY5Y cells from mitochondrial dysfunction and cell death caused by MPP+ treatment, via the AMPK-PGC-1α axis. These findings also suggest that fucoidan could potentially be used as a therapeutic agent for PD.


Assuntos
1-Metil-4-fenilpiridínio/farmacologia , Morte Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Neurônios/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Polissacarídeos/farmacologia , Adenilato Quinase/metabolismo , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Neurônios/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo
7.
Nat Commun ; 10(1): 3945, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477726

RESUMO

Neuroinflammation is one of the hallmarks of Parkinson's disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD - to modulate disease progression - still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.


Assuntos
Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/administração & dosagem , Inflamação/prevenção & controle , Degeneração Neural/prevenção & controle , Doença de Parkinson/prevenção & controle , Animais , Ácidos Docosa-Hexaenoicos/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
8.
J Biochem ; 166(6): 463-474, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31385584

RESUMO

Parkinsonism-linked mutations in alanine and glutamic acid residues of the pre-synaptic protein α-Synuclein (α-Syn) affect specific tertiary interactions essential for stability of the native state and make it prone to more aggregation. Many of the currently available drugs used for the treatment of Parkinson's disease (PD) are not very effective and are associated with multiple side effects. Recently, marine algae have been reported to have sulphated polysaccharides which offers multiple pharmaceutical properties. With this background, we have isolated sulphated polysaccharides from Chlamydomonas reinhardtii (Cr-SPs) and investigated their effects on inhibition of fibrillation/aggregation of α-Syn mutants through a combination of spectroscopic and microscopic techniques. The kinetics of α-Syn fibrillation establishes that Cr-SPs are very effective in inhibiting fibrillation of α-Syn mutants. The morphological changes associated with the fibrillation/aggregation process have been monitored by transmission electron microscopy. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis gel image suggests that Cr-SPs increase the amount of soluble protein after completion of the fibrillation/aggregation process. The circular dichroism results showed that Cr-SPs efficiently delay the conversion of native protein into ß-sheet-rich structures. Thus, the current work has considerable therapeutic implications towards deciphering the potential of Cr-SPs to act against PD and other protein aggregation-related disorders.


Assuntos
Chlamydomonas reinhardtii/química , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Polissacarídeos/farmacologia , alfa-Sinucleína/antagonistas & inibidores , Humanos , Mutação , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Doença de Parkinson/metabolismo , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Agregados Proteicos/efeitos dos fármacos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
9.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31405050

RESUMO

Compelling evidence supports a tight link between oxidative stress and protein aggregation processes, which are noticeably involved in the development of proteinopathies, such as Alzheimer's disease, Parkinson's disease, and prion disease. The literature is tremendously rich in studies that establish a functional link between both processes, revealing that oxidative stress can be either causative, or consecutive, to protein aggregation. Because oxidative stress monitoring is highly challenging and may often lead to artefactual results, cutting-edge technical tools have been developed recently in the redox field, improving the ability to measure oxidative perturbations in biological systems. This review aims at providing an update of the previously known functional links between oxidative stress and protein aggregation, thereby revisiting the long-established relationship between both processes.


Assuntos
Estresse Oxidativo , Agregação Patológica de Proteínas/metabolismo , Proteínas/metabolismo , Doença de Alzheimer/metabolismo , Animais , Humanos , Doença de Parkinson/metabolismo , Doenças Priônicas/metabolismo , Agregados Proteicos
10.
Immunopharmacol Immunotoxicol ; 41(4): 469-476, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31405314

RESUMO

The extracellular vesicles (EVs) represent a relatively new field of research in neurodegenerative disease and they are thought to be one of the ways that neurodegenerative pathologies, such as Parkinson's Disease (PD), spread in the brain. EVs are membrane vesicles released from cells into the extracellular space and they are produced by all cells of the nervous tissue. The classification of the vesicle subtypes comprises exosomes, microvesicles/microparticles, apoptotic bodies. EVs change in number and content in response to environmental conditions and may function as shuttles for the delivery of cargo between cells. Recent data suggest that exosomes secreted by both activated microglia and neurons play an important role in α-synuclein (α-syn) spreading and increase of neuroinflammation, thus exacerbating neuronal dysfunction and disease progression. α-syn is a presynaptic protein secreted by neurons in small amounts, and it is the main component of Lewy bodies, one of the histopathological features of PD. Several factors have shown to induce and/or modulate α-syn structure and oligomerization in vitro. Under pathological conditions, progressive accumulation of α-syn and the formation of oligomers have been proposed to play a critical role in the pathogenesis of PD. This review gives an overview about the multiple roles of exosomes in PD, despite their role in the progression of neurodegeneration, exosomes could represent a specific drug delivery tool for a difficult target such as the brain, which poses an obstacle to most drugs and they could also represent new biomarkers to track the progression of PD.


Assuntos
Exossomos/patologia , Doença de Parkinson/patologia , Animais , Biomarcadores/metabolismo , Progressão da Doença , Exossomos/metabolismo , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doença de Parkinson/metabolismo
11.
Neurology ; 93(7): 302-309, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31405935

RESUMO

OBJECTIVE: To test the hypothesis that myoclonus in patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C) is associated with a heavier burden of α-synuclein deposition in the motor regions of the spinal cord, we compared the degree of α-synuclein deposition in spinal cords of 3 patients with MSA-C with myoclonus and 3 without myoclonus. METHODS: All human tissue was obtained by the Massachusetts General Hospital Department of Pathology with support from and according to neuropathology guidelines of the Massachusetts Alzheimer's Disease Research Center. Tissue was stained with Luxol fast blue and hematoxylin & eosin for morphologic evaluation, and with a mouse monoclonal antibody to α-synuclein and Vectastain DAB kit. Images of the spinal cord sections were digitized using a 10× objective lens. Grayscale versions of these images were transferred to ImageJ software for quantitative analysis of 8 different regions of interest (ROIs) in the spinal cord: dorsal column, anterior white column, left and right dorsal horns, left and right anterior horns, and left and right lateral corticospinal tracts. A mixed-effect, multiple linear regression model was constructed to determine if patients with and without myoclonus had significantly different distributions of α-synuclein deposition across the various ROIs. RESULTS: Patients with myoclonus had more α-synuclein in the anterior horns (p < 0.001) and lateral corticospinal tracts (p = 0.02) than those without myoclonus. CONCLUSIONS: In MSA-C, myoclonus appears to be associated with a higher burden of α-synuclein deposition within spinal cord motor regions. Future studies with more patients will be needed to confirm these findings.


Assuntos
Atrofia de Múltiplos Sistemas/patologia , Mioclonia/metabolismo , Medula Espinal/patologia , alfa-Sinucleína/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/complicações , Mioclonia/complicações , Doença de Parkinson/complicações , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Medula Espinal/metabolismo
12.
Int J Mol Sci ; 20(17)2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31450864

RESUMO

Parkinson's disease (PD) is a complex neurological disorder classically characterized by impairments in motor system function associated with loss of dopaminergic neurons in the substantia nigra. After almost 200 years since the first description of PD by James Parkinson, unraveling the complexity of PD continues to evolve. It is now recognized that an interplay between genetic and environmental factors influences a diverse range of cellular processes, reflecting on other clinical features including non-motor symptoms. This has consequently highlighted the extensive value of early clinical diagnosis to reduce difficulties of later stage management of PD. Advancement in understanding of PD has made remarkable progress in introducing new tools and strategies such as stem cell therapy and deep brain stimulation. A link between alterations in gut microbiota and PD has also opened a new line. Evidence exists of a bidirectional pathway between the gastrointestinal tract and the central nervous system. Probiotics, prebiotics and synbiotics are being examined that might influence gut-brain axis by altering gut microbiota composition, enteric nervous system, and CNS. This review provides status on use of probiotics for PD. Limitations and future directions will also be addressed to promote further research considering use of probiotics for PD.


Assuntos
Doença de Parkinson/dietoterapia , Probióticos/uso terapêutico , Animais , Encéfalo/metabolismo , Disbiose , Sistema Nervoso Entérico/metabolismo , Microbioma Gastrointestinal , Trato Gastrointestinal/inervação , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Humanos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Transdução de Sinais , Simbióticos
13.
Biochim Biophys Acta Proteins Proteom ; 1867(11): 140264, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31437584

RESUMO

Protein amyloid aggregation is a hallmark in neuropathologies and other diseases of tremendous impact such as Alzheimer's or Parkinson's diseases. During the last decade, it has become increasingly evident that neuronal death is mainly induced by proteinaceous oligomers rather than the mature amyloid fibrils. Therefore, the earliest molecular events occurring during the amyloid aggregation cascade represent a growing interest of study. Important breakthroughs have been achieved using experimental data from different proteins, used as models, as well as systems related to diseases. Here, we summarize the structural properties of amyloid oligomeric and fibrillar aggregates and review the recent advances on how biophysical techniques can be combined with quantitative kinetic analysis and theoretical models to study the detailed mechanism of oligomer formation and nucleation of fibrils. These insights into the mechanism of early oligomerization and amyloid nucleation are of relevant interest in drug discovery and in the design of preventive strategies against neurodegenerative diseases.


Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Modelos Biológicos , Modelos Moleculares , Doença de Parkinson/metabolismo , Agregados Proteicos , Amiloide/química , Humanos
14.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416122

RESUMO

Accumulation of α-synuclein (α-Syn) is a remarkable pathology for Parkinson's disease (PD), therefore clearing it is possibly a promising strategy for treating PD. Aberrant copper (Cu(II)) homeostasis and oxidative stress play critical roles in the abnormal aggregation of α-Syn in the progress of PD. It is reported that the polyphenol (-)-epi-gallocatechin gallate (EGCG) can inhibit α-Syn fibrillation and aggregation, disaggregate α-Syn mature fibrils, as well as protect α-Syn overexpressed-PC12 cells against damage. Also, previous studies have reported that EGCG can chelate many divalent metal ions. What we investigate here is whether EGCG can interfere with the Cu(II) induced fibrillation of α-Syn and protect the cell viability. In this work, on a molecular and cellulaire basis, we demonstrated that EGCG can form a Cu(II)/EGCG complex, leading to the inhibition of Cu(II)-induced conformation transition of α-Syn from random coil to ß-sheet, which is a dominant structure in α-Syn fibrils and aggregates. Moreover, we found that the mixture of Cu(II) and EGCG in a molar ratio from 0.5 to 2 can efficiently inhibit this process. Furthermore, we demonstrated that in the α-Syn transduced-PC12 cells, EGCG can inhibit the overexpression and fibrillation of α-Syn in the cells, and reduce Cu(II)-induced reactive oxygen species (ROS), protecting the cells against Cu(II)-mediated toxicity.


Assuntos
Proteínas Amiloidogênicas/metabolismo , Catequina/análogos & derivados , Cobre , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , Proteínas Amiloidogênicas/química , Animais , Catequina/química , Catequina/farmacologia , Linhagem Celular , Cobre/química , Cobre/toxicidade , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ressonância Magnética Nuclear Biomolecular , Estresse Oxidativo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/tratamento farmacológico , Ratos , Espécies Reativas de Oxigênio/metabolismo , alfa-Sinucleína/química
15.
Int J Mol Sci ; 20(15)2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31382686

RESUMO

Lipids in the brain are major components playing structural functions as well as physiological roles in nerve cells, such as neural communication, neurogenesis, synaptic transmission, signal transduction, membrane compartmentalization, and regulation of gene expression. Determination of brain lipid composition may provide not only essential information about normal brain functioning, but also about changes with aging and diseases. Indeed, deregulations of specific lipid classes and lipid homeostasis have been demonstrated in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, recent studies have shown that membrane microdomains, named lipid rafts, may change their composition in correlation with neuronal impairment. Lipid rafts are key factors for signaling processes for cellular responses. Lipid alteration in these signaling platforms may correlate with abnormal protein distribution and aggregation, toxic cell signaling, and other neuropathological events related with these diseases. This review highlights the manner lipid changes in lipid rafts may participate in the modulation of neuropathological events related to AD and PD. Understanding and characterizing these changes may contribute to the development of novel and specific diagnostic and prognostic biomarkers in routinely clinical practice.


Assuntos
Envelhecimento/metabolismo , Lipídeos/genética , Microdomínios da Membrana/metabolismo , Doenças Neurodegenerativas/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Microdomínios da Membrana/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Transdução de Sinais/genética
16.
Sleep Med Clin ; 14(3): 351-362, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31375203

RESUMO

In recent years, the diagnostic approach to rapid eye movement (REM) sleep behavior disorder (RBD) has become more objective and accurate. This was achieved mainly by introduction of methods to exactly quantify electromyographic (EMG) activity in various muscles during REM sleep. The most established muscle combination for RBD diagnosis is the mentalis and upper extremity EMG. Computer-assisted systems for this analysis have been described, and an increasing number of studies looked into analysis of video events. Recently, prodromal phases of isolated RBD have been recognized.


Assuntos
Eletromiografia , Polissonografia , Transtorno do Comportamento do Sono REM/diagnóstico , Progressão da Doença , Humanos , Processamento de Imagem Assistida por Computador , Mucosa Intestinal/metabolismo , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/fisiopatologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Medicina de Precisão , Sintomas Prodrômicos , Transtorno do Comportamento do Sono REM/metabolismo , Transtorno do Comportamento do Sono REM/fisiopatologia , Glândulas Salivares/metabolismo , Pele/metabolismo , Sono REM , /fisiopatologia , Gravação em Vídeo , alfa-Sinucleína/metabolismo
17.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295812

RESUMO

Alzheimer's disease (AD), which is characterized by the presence of amyloid-ß (Aß) plaques and neurofibrillary tangles, accompanied by neurodegeneration, is the most common form of age-related neurodegenerative disease. Parkinson's disease (PD) is the second most common neurodegenerative disease after AD, and is characterized by early prominent loss of dopaminergic neurons in the substantia nigra pars compacta. As currently available treatments are not able to significantly alter the progression of these diseases, successful therapeutic and preventive interventions are strongly needed. In the course of our survey of substances from natural resources having anti-dementia and neuroprotective activity, we found nobiletin, a polymethoxylated flavone from the peel of Citrus depressa. Nobiletin improved cognitive deficits and the pathological features of AD, such as Aß pathology, hyperphosphorylation of tau, and oxidative stress, in animal models of AD. In addition, nobiletin improved motor and cognitive deficits in PD animal models. These observations suggest that nobiletin has the potential to become a novel drug for the treatment and prevention of neurodegenerative diseases such as AD and PD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Citrus/química , Flavonas/farmacologia , Flavonoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Biomarcadores , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Flavonas/química , Flavonas/uso terapêutico , Flavonoides/química , Flavonoides/uso terapêutico , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/prevenção & controle , Transdução de Sinais/efeitos dos fármacos
18.
Nutrients ; 11(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331066

RESUMO

Vasicinone is a quinazoline alkaloid isolated from the Adhatoda vasica plant. In this study, we explored the neuroprotective effect and underlying molecular mechanism of vasicinone against paraquat-induced cellular apoptosis in SH-SY5Y cells. Vasicinone reduced the paraquat-induced loss of cell viability, rescued terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic nuclei, and suppressed generation of reactive oxygen species (ROS) in a dose-dependent manner. Western blotting analysis revealed that vasicinone increased the phosphorylation of IGF1R/PI3K/AKT cell survival signaling molecules and downregulated the paraquat-induced, mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)-mediated apoptotic pathways compared to that observed in cells not treated with vasicinone. This protection depended critically on the activation of IGF1R, and the silencing of IGF1R by siRNA completely abrogated the protective effect of vasicinone in SH-SY5Y cells. Our findings indicated that vasicinone is a potential candidate for the treatment of Parkinson's disease and possibly other oxidative stress-related neurodegenerative disorders.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Paraquat/farmacologia , Doença de Parkinson , Fosfatidilinositol 3-Quinases/metabolismo , Receptor IGF Tipo 1/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Marcação In Situ das Extremidades Cortadas , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo
19.
Neurology ; 93(7): e665-e674, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31289143

RESUMO

OBJECTIVE: To investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD). METHODS: Using data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2). RESULTS: GRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = -0.128, p = 0.019; GRS2, Spearman ρ = -0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016). CONCLUSIONS: Our results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression-specific GRS may be useful in predicting disease progression in patients.


Assuntos
Corpo Estriado/metabolismo , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/metabolismo , Tropanos/metabolismo , Adulto , Idoso , Núcleo Caudado/metabolismo , Progressão da Doença , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/genética , Transtornos Parkinsonianos/complicações , Putamen/metabolismo
20.
Int J Mol Sci ; 20(13)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284408

RESUMO

Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide-sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann-Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson's disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson's disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies.


Assuntos
Doença de Gaucher/metabolismo , Doença de Parkinson/metabolismo , Esfingolipídeos/metabolismo , Animais , Vias Biossintéticas , Enzimas/metabolismo , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Esfingolipídeos/biossíntese , Esfingolipídeos/química
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