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1.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443430

RESUMO

Parkinson's disease (PD) is a currently incurable neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and α-synuclein aggregation. Accumulated evidence indicates that the saponins, especially from ginseng, have neuroprotective effects against neurodegenerative disorders. Interestingly, saponin can also be found in marine organisms such as the sea cucumber, but little is known about its effect in neurodegenerative disease, including PD. In this study, we investigated the anti-Parkinson effects of frondoside A (FA) from Cucumaria frondosa and ginsenoside Rg3 (Rg3) from Panax notoginseng in C. elegans PD model. Both saponins were tested for toxicity and optimal concentration by food clearance assay and used to treat 6-OHDA-induced BZ555 and transgenic α-synuclein NL5901 strains in C. elegans. Treatment with FA and Rg3 significantly attenuated DAergic neurodegeneration induced by 6-OHDA in BZ555 strain, improved basal slowing rate, and prolonged lifespan in the 6-OHDA-induced wild-type strain with downregulation of the apoptosis mediators, egl-1 and ced-3, and upregulation of sod-3 and cat-2. Interestingly, only FA reduced α-synuclein aggregation, rescued lifespan in NL5901, and upregulated the protein degradation regulators, including ubh-4, hsf-1, hsp-16.1 and hsp-16.2. This study indicates that both FA and Rg3 possess beneficial effects in rescuing DAergic neurodegeneration in the 6-OHDA-induced C. elegans model through suppressing apoptosis mediators and stimulating antioxidant enzymes. In addition, FA could attenuate α-synuclein aggregation through the protein degradation process.


Assuntos
Caenorhabditis elegans/fisiologia , Ginsenosídeos/farmacologia , Glicosídeos/farmacologia , Doença de Parkinson/patologia , Triterpenos/farmacologia , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/química , Ginsenosídeos/toxicidade , Glicosídeos/química , Glicosídeos/toxicidade , Longevidade/efeitos dos fármacos , Degeneração Neural/complicações , Degeneração Neural/patologia , Oxidopamina , Doença de Parkinson/complicações , Proteólise/efeitos dos fármacos , Triterpenos/química , Triterpenos/toxicidade , alfa-Sinucleína/metabolismo
2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360942

RESUMO

The exact mechanism underlying selective dopaminergic neurodegeneration is not completely understood. The complex interplay among toxic alpha-synuclein aggregates, oxidative stress, altered intracellular Ca2+-homeostasis, mitochondrial dysfunction and disruption of mitochondrial integrity is considered among the pathogenic mechanisms leading to dopaminergic neuronal loss. We herein investigated the molecular mechanisms leading to mitochondrial dysfunction and its relationship with activation of the neuroinflammatory process occurring in Parkinson's disease. To address these issues, experiments were performed in vitro and in vivo in mice carrying the human mutation of α-synuclein A53T under the prion murine promoter. In these models, the expression and activity of NCX isoforms, a family of important transporters regulating ionic homeostasis in mammalian cells working in a bidirectional way, were evaluated in neurons and glial cells. Mitochondrial function was monitored with confocal microscopy and fluorescent dyes to measure mitochondrial calcium content and mitochondrial membrane potential. Parallel experiments were performed in 4 and 16-month-old A53T-α-synuclein Tg mice to correlate the functional data obtained in vitro with mitochondrial dysfunction and neuroinflammation through biochemical analysis. The results obtained demonstrated: 1. in A53T mice mitochondrial dysfunction occurs early in midbrain and later in striatum; 2. mitochondrial dysfunction occurring in the midbrain is mediated by the impairment of NCX3 protein expression in neurons and astrocytes; 3. mitochondrial dysfunction occurring early in midbrain triggers neuroinflammation later into the striatum, thus contributing to PD progression during mice aging.


Assuntos
Mesencéfalo/metabolismo , Mitocôndrias/metabolismo , Doença de Parkinson/metabolismo , Trocador de Sódio e Cálcio/metabolismo , alfa-Sinucleína/genética , Animais , Astrócitos/metabolismo , Cálcio/metabolismo , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Mesencéfalo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Doença de Parkinson/genética , Trocador de Sódio e Cálcio/genética , alfa-Sinucleína/metabolismo
3.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360787

RESUMO

The principal pathogenic event in Parkinson's disease is characterized by the conformational change of α-synuclein, which form pathological aggregates of misfolded proteins, and then accumulate in intraneuronal inclusions causing dopaminergic neuronal loss in specific brain regions. Over the last few years, a revolutionary theory has correlated Parkinson's disease and other neurological disorders with a shared mechanism, which determines α-synuclein aggregates and progresses in the host in a prion-like manner. In this review, the main characteristics shared between α-synuclein and prion protein are compared and the cofactors that influence the remodeling of native protein structures and pathogenetic mechanisms underlying neurodegeneration are discussed.


Assuntos
Doença de Parkinson , Doenças Priônicas , Agregados Proteicos , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia
4.
Nat Commun ; 12(1): 4863, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381050

RESUMO

Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer's disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.


Assuntos
Clusterina/metabolismo , Agregação Patológica de Proteínas/metabolismo , Proteínas tau/metabolismo , Animais , Clusterina/genética , Progressão da Doença , Endocitose , Humanos , Camundongos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Neurônios/patologia , Agregação Patológica de Proteínas/patologia , Ligação Proteica , alfa-Sinucleína/metabolismo , Proteínas tau/genética
5.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361100

RESUMO

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson's disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.


Assuntos
Doença de Parkinson/patologia , Príons/metabolismo , Agregação Patológica de Proteínas , alfa-Sinucleína/metabolismo , Animais , Humanos , Doença de Parkinson/metabolismo
6.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361780

RESUMO

Parkinson's disease is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) and the resultant loss of dopamine in the striatum. Various studies have shown that oxidative stress and neuroinflammation plays a major role in PD progression. In addition, the autophagy lysosome pathway (ALP) plays an important role in the degradation of aggregated proteins, abnormal cytoplasmic organelles and proteins for intracellular homeostasis. Dysfunction of ALP results in the accumulation of α-synuclein and the loss of dopaminergic neurons in PD. Thus, modulating ALP is becoming an appealing therapeutic intervention. In our current study, we wanted to evaluate the neuroprotective potency of noscapine in a rotenone-induced PD rat model. Rats were administered rotenone injections (2.5 mg/kg, i.p.,) daily followed by noscapine (10 mg/kg, i.p.,) for four weeks. Noscapine, an iso-qinulinin alkaloid found naturally in the Papaveraceae family, has traditionally been used in the treatment of cancer, stroke and fibrosis. However, the neuroprotective potency of noscapine has not been analyzed. Our study showed that administration of noscapine decreased the upregulation of pro-inflammatory factors, oxidative stress, and α-synuclein expression with a significant increase in antioxidant enzymes. In addition, noscapine prevented rotenone-induced activation of microglia and astrocytes. These neuroprotective mechanisms resulted in a decrease in dopaminergic neuron loss in SNpc and neuronal fibers in the striatum. Further, noscapine administration enhanced the mTOR-mediated p70S6K pathway as well as inhibited apoptosis. In addition to these mechanisms, noscapine prevented a rotenone-mediated increase in lysosomal degradation, resulting in a decrease in α-synuclein aggregation. However, further studies are needed to further develop noscapine as a potential therapeutic candidate for PD treatment.


Assuntos
Autofagia/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Noscapina/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/genética , Parte Compacta da Substância Negra/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Catalase/genética , Catalase/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Rotenona/toxicidade , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , alfa-Sinucleína/antagonistas & inibidores , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
7.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204581

RESUMO

Parkinson's disease (PD) is considered the most common disorder of synucleinopathy, which is characterised by intracellular inclusions of aggregated and misfolded α-synuclein (α-syn) protein in various brain regions, and the loss of dopaminergic neurons. During the early prodromal phase of PD, synaptic alterations happen before cell death, which is linked to the synaptic accumulation of toxic α-syn specifically in the presynaptic terminals, affecting neurotransmitter release. The oligomers and protofibrils of α-syn are the most toxic species, and their overexpression impairs the distribution and activation of synaptic proteins, such as the SNARE complex, preventing neurotransmitter exocytosis and neuronal synaptic communication. In the last few years, the role of the immune system in PD has been increasingly considered. Microglial and astrocyte activation, the gene expression of proinflammatory factors, and the infiltration of immune cells from the periphery to the central nervous system (CNS) represent the main features of the inflammatory response. One of the actors of these processes is α-syn accumulation. In light of this, here, we provide a systematic review of PD-related α-syn and inflammation inter-players.


Assuntos
Suscetibilidade a Doenças , Doença de Parkinson/metabolismo , Sinapses/metabolismo , alfa-Sinucleína/metabolismo , Imunidade Adaptativa , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Imunidade Inata , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Sinapses/imunologia , alfa-Sinucleína/genética
8.
Handb Clin Neurol ; 182: 235-244, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34266595

RESUMO

Lewy bodies are intraneuronal eosinophilic cytoplasmic inclusions, and their presence in the specific areas of the central nervous system defines the so-called Lewy body disorders such as Parkinson's disease and dementia with Lewy bodies. The protein alpha-synuclein is the major component of Lewy bodies and there is evidence suggesting that it is capable of spreading from cell to cell within the central nervous system thereby propagating the pathological process. The olfactory system, particularly the olfactory bulb, is almost always affected in Parkinson's disease and dementia with Lewy bodies. Moreover, in Parkinson's disease, the olfactory bulb is involved by Lewy pathology at very early stages of the disease. The hypothalamus is also compromised by Lewy pathology in the course of Parkinson's disease; however, unlike the olfactory system in which most regions of the primary olfactory cortex become affected, there is a selective vulnerability of certain hypothalamic regions including the tuberomamillary nucleus, the lateral tuberal nucleus, and orexin/hypocretin neurons, while other nuclear groups remain free of Lewy pathology even in the advanced stages of the disease.


Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Humanos , Hipotálamo/metabolismo , Corpos de Lewy , alfa-Sinucleína/metabolismo
9.
Neuroscience ; 469: 91-102, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34216695

RESUMO

The transport mechanism of intestinal α-synuclein to the central nervous system has become a new hot topic in Parkinson's disease (PD) research. It is worth noting that the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been reported to be involved in the pathogenesis of PD. After silencing GAPDH expression by GAPDH siRNA, the normal human intestinal epithelial crypt-like (HIEC) and human SH-SY5Y neuroblastoma cell lines were co-cultured with Escherichia coli cells which were transfected with an α-synuclein overexpression plasmid. The levels of autophagy-related proteins (BECN1, ATG5, LC3A/B and p62) were determined by Western blot analysis. Changes in pro-apoptosis protein levels and flow cytometry analysis were used to assess cell apoptosis and relative intracellular ATP concentration was measured. Oxidative stress was assessed by measuring the levels of reactive oxygen species (ROS) using 2',7'-dichlorofluorescein diacetate (DCFH-DA), thiobarbituric acid-reactive substances (TBARS), and antioxidant capacity was assessed by measuring the glutathione (GSH) levels and superoxide dismutase (SOD) activity. The silencing of the expression of GAPDH pre-knockdown was found to reduce the intracellular levels of ROS and lipid peroxidation, enhance autophagy activity, thereby reducing the cell injury, apoptosis and necrosis induced by exogenous α-synuclein protein in SH-SY5Y cells. This study identifies a new therapeutic target of exogenous α-synuclein protein induced SH-SY5Y cell injury and improves our understanding of the pathophysiological role of GAPDH in vitro.


Assuntos
Apoptose , Gliceraldeído-3-Fosfato Desidrogenases , alfa-Sinucleína , Linhagem Celular Tumoral , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Estresse Oxidativo , RNA Interferente Pequeno , alfa-Sinucleína/metabolismo
10.
Gene ; 799: 145811, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34224829

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in the eye of A30P fly PD model. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.


Assuntos
Carotenoides/farmacologia , Crocus/química , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/etiologia , Degeneração Retiniana/tratamento farmacológico , Vitamina A/análogos & derivados , Animais , Animais Geneticamente Modificados , Linhagem Celular , Modelos Animais de Doenças , Drosophila melanogaster/genética , Feminino , Humanos , Longevidade/efeitos dos fármacos , Masculino , Mutação , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Degeneração Retiniana/etiologia , Degeneração Retiniana/fisiopatologia , Vitamina A/farmacologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidade
11.
J Chem Theory Comput ; 17(8): 5276-5286, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34261315

RESUMO

Membrane curvature plays an essential role in the organization and trafficking of membrane associated proteins. Comparison or prediction of the experimentally resolved protein concentrations adopted at different membrane curvatures requires direct quantification of the relative partitioning free energy. Here, we present a highly efficient and simple to implement a free-energy calculation method which is able to directly resolve the relative partitioning free energy of proteins as a direct function of membrane curvature, i.e., a curvature sensing profile, within (coarse-grained) molecular dynamics simulations. We demonstrate its utility by resolving these profiles for two known curvature sensing peptides, namely ALPS and α-synuclein, for a membrane curvature ranging from -1/6.5 to +1/6.5 nm-1. We illustrate that the difference in relative partitioning (binding) free energy between these two extrema is only about 13 kBT for both peptides, illustrating that the driving force of curvature sensing is subtle. Furthermore, we illustrate that ALPS and α-synuclein sense curvature via a contrasting mechanism, which is differentially affected by membrane composition. In addition, we demonstrate that the intrinsic spontaneous curvature of both of these peptides lies beyond the range of membrane curvature accessible in micropipette aspiration experiments, being about 1/7 nm -1. Our approach offers an efficient and simple to implement in silico tool for exploring and screening the membrane curvature sensing mechanisms of proteins.


Assuntos
alfa-Sinucleína/química , Motivos de Aminoácidos , Cinética , Simulação de Dinâmica Molecular , alfa-Sinucleína/metabolismo
12.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299000

RESUMO

Parkinson's disease (PD) is the most common movement disorder, characterized by progressive degeneration of the nigrostriatal pathway, which consists of dopaminergic cell bodies in substantia nigra and their neuronal projections to the striatum. Moreover, PD is associated with an array of non-motor symptoms such as olfactory dysfunction, gastrointestinal dysfunction, impaired regulation of the sleep-wake cycle, anxiety, depression, and cognitive impairment. Inflammation and concomitant oxidative stress are crucial in the pathogenesis of PD. Thus, this study aimed to model PD via intrastriatal injection of the inflammagen lipopolysaccharide (LPS)to investigate if the lesion causes olfactory and motor impairments, inflammation, oxidative stress, and alteration in synaptic proteins in the olfactory bulb, striatum, and colon. Ten µg of LPS was injected unilaterally into the striatum of 27 male C57BL/6 mice, and behavioural assessment was conducted at 4 and 8 weeks post-treatment, followed by tissue collection. Intrastriatal LPS induced motor impairment in C57BL/6 mice at 8 weeks post-treatment evidenced by reduced latency time in the rotarod test. LPS also induced inflammation in the striatum characterized by increased expression of microglial marker Iba-1 and astrocytic marker GFAP, with degeneration of dopaminergic neuronal fibres (reduced tyrosine hydroxylase immunoreactivity), and reduction of synaptic proteins and DJ-1 protein. Additionally, intrastriatal LPS induced inflammation, oxidative stress and alterations in synaptic proteins within the olfactory bulb, although this did not induce a significant impairment in olfactory function. Intrastriatal LPS induced mild inflammatory changes in the distal colon, accompanied by increased protein expression of 3-nitrotyrosine-modified proteins. This model recapitulated the major features of PD such as motor impairment and degeneration of dopaminergic neuronal fibres in the striatum, as well as some pathological changes in the olfactory bulb and colon; thus, this model could be suitable for understanding clinical PD and testing neuroprotective strategies.


Assuntos
Astrócitos/metabolismo , Colo/metabolismo , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Lipopolissacarídeos/metabolismo , Bulbo Olfatório/metabolismo , Doença de Parkinson/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Escala de Avaliação Comportamental , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Colo/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microglia/metabolismo , Microglia/patologia , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/patologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/patologia , Doença de Parkinson/psicologia , Proteína Desglicase DJ-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
13.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199487

RESUMO

Phenolic compounds are thought to be important to prevent neurodegenerative diseases (ND). Parkinson's Disease (PD) is a neurodegenerative disorder known for its typical motor features, the deposition of α-synuclein (αsyn)-positive inclusions in the brain, and for concomitant cellular pathologies that include oxidative stress and neuroinflammation. Neuroprotective activity of fisetin, a dietary flavonoid, was evaluated against main hallmarks of PD in relevant cellular models. At physiologically relevant concentrations, fisetin protected SH-SY5Y cells against oxidative stress overtaken by tert-butyl hydroperoxide (t-BHP) and against methyl-4-phenylpyridinuim (MPP+)-induced toxicity in dopaminergic neurons, the differentiated Lund human Mesencephalic (LUHMES) cells. In this cellular model, fisetin promotes the increase of the levels of dopamine transporter. Remarkably, fisetin reduced the percentage of cells containing αsyn inclusions as well as their size and subcellular localization in a yeast model of αsyn aggregation. Overall, our data show that fisetin exerts modulatory activities toward common cellular pathologies present in PD; remarkably, it modulates αsyn aggregation, supporting the idea that diets rich in this compound may prove beneficial.


Assuntos
Butiratos/efeitos adversos , Flavonóis/farmacologia , Doença de Parkinson/metabolismo , Piperidinas/efeitos adversos , alfa-Sinucleína/metabolismo , Linhagem Celular , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Modelos Biológicos , Estresse Oxidativo , Doença de Parkinson/tratamento farmacológico , Agregados Proteicos/efeitos dos fármacos , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , terc-Butil Hidroperóxido/metabolismo
14.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207975

RESUMO

Molecular studies have provided increasing evidence that Parkinson's disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function-e.g., sphingosine-1-phosphate (S1P) and ceramide-is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the "sphingolipid biostat" favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P-a potent lipid mediator regulating cell fate and inflammatory response-making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD.


Assuntos
Doença de Parkinson/metabolismo , Transdução de Sinais , alfa-Sinucleína/metabolismo , Animais , Humanos , Lisofosfolipídeos/metabolismo , Terapia de Alvo Molecular , Neuroproteção , Doença de Parkinson/etiologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo , alfa-Sinucleína/toxicidade
15.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299248

RESUMO

Parkinson's disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5-1% among those aged 65-70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration-for instance, alpha-synuclein accumulation-and finally neuronal death.


Assuntos
Metabolismo dos Lipídeos/genética , Lipídeos/fisiologia , Doença de Parkinson/genética , Neurônios Dopaminérgicos/metabolismo , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Fosfolipases A2 do Grupo VI/genética , Fosfolipases A2 do Grupo VI/metabolismo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Degeneração Neural/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-34206224

RESUMO

Quadruple aberrant hyperphosphorylated tau (p-τ), amyloid-ß peptide, alpha-synuclein and TDP-43 brainstem and supratentorial pathology are documented in forensic ≤40y autopsies in Metropolitan Mexico City (MMC), and p-τ is the major aberrant protein. Post-traumatic stress disorder (PTSD) is associated with an elevated risk of subsequent dementia, and rapid eye movement sleep behavior disorder (RBD) is documented in PD, AD, Lewy body dementia and ALS. This study aimed to identify an association between PTSD and potential pRBD in Mexico. An anonymous online survey of 4502 urban college-educated adults, 29.3 ± 10.3 years; MMC, n = 1865; non-MMC, n = 2637, measured PTSD symptoms using the Impact of Event Scale-Revised (IES-R) and pRBD symptoms using the RBD Single-Question. Over 50% of the participants had IES-R scores ≥33 indicating probable PTSD. pRBD was identified in 22.6% of the participants across Mexico and 32.7% in MMC residents with PTSD. MMC subjects with PTSD had an OR 2.6218 [2.5348, 2.7117] of answering yes to the pRBD. PTSD and pRBD were more common in women. This study showed an association between PTSD and pRBD, strengthening the possibility of a connection with misfolded proteinopathies in young urbanites. We need to confirm the RBD diagnosis using an overnight polysomnogram. Mexican women are at high risk for stress and sleep disorders.


Assuntos
Transtorno do Comportamento do Sono REM , alfa-Sinucleína , Adulto , Peptídeos beta-Amiloides , Tronco Encefálico , Proteínas de Ligação a DNA , Feminino , Humanos , México/epidemiologia , Sono , alfa-Sinucleína/metabolismo
17.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201785

RESUMO

Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson's disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2G2019S) was sufficient to induce neurodegeneration of DA neurons in vivo, suggesting that mutated LRRK2 induces neurotoxicity through mechanisms that are (i) independent of the N-terminal domains and (ii) "cell-autonomous". Here, we explored whether ΔLRRK2G2019S could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2G2019S or its "dead" kinase form, ΔLRRK2DK, and human α-syn with the A53T mutation (AAV-α-synA53T). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of ΔLRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-α-synA53T alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-synA53T with AAV-ΔLRRK2G2019S induced DA neuron degeneration that was significantly higher than that induced by AAV-α-synA53T alone or with AAV-ΔLRRK2DK. Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2G2019 alone, through cell-autonomous mechanisms.


Assuntos
Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Proteínas Mutantes/metabolismo , Mutação , alfa-Sinucleína/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Proteínas Mutantes/genética , Domínios Proteicos , Ratos , alfa-Sinucleína/genética
18.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208778

RESUMO

Parkinson's disease (PD) is a proteinopathy associated with the aggregation of α-synuclein and the formation of lipid-protein cellular inclusions, named Lewy bodies (LBs). LB formation results in impaired neurotransmitter release and uptake, which involve membrane traffic and require lipid synthesis and metabolism. Lipids, particularly ceramides, are accumulated in postmortem PD brains and altered in the plasma of PD patients. Autophagy is impaired in PD, reducing the ability of neurons to clear protein aggregates, thus worsening stress conditions and inducing neuronal death. The inhibition of ceramide synthesis by myriocin (Myr) in SH-SY5Y neuronal cells treated with preformed α-synuclein fibrils reduced intracellular aggregates, favoring their sequestration into lysosomes. This was associated with TFEB activation, increased expression of TFEB and LAMP2, and the cytosolic accumulation of LC3II, indicating that Myr promotes autophagy. Myr significantly reduces the fibril-related production of inflammatory mediators and lipid peroxidation and activates NRF2, which is downregulated in PD. Finally, Myr enhances the expression of genes that control neurotransmitter transport (SNARE complex, VMAT2, and DAT), whose progressive deficiency occurs in PD neurodegeneration. The present study suggests that counteracting the accumulation of inflammatory lipids could represent a possible therapeutic strategy for PD.


Assuntos
Ceramidas/biossíntese , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , Vias Biossintéticas/efeitos dos fármacos , Linhagem Celular Tumoral , Gerenciamento Clínico , Suscetibilidade a Doenças , Ácidos Graxos Monoinsaturados/metabolismo , Humanos , Espaço Intracelular/metabolismo , Estresse Oxidativo , Doença de Parkinson/tratamento farmacológico , Esfingolipídeos/metabolismo
19.
Nat Commun ; 12(1): 3817, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155194

RESUMO

α-Synuclein is critical in the pathogenesis of Parkinson's disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson's disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson's disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson's disease-associated genes influence the phenotypic manifestation of strains in human neurons.


Assuntos
Neurônios Dopaminérgicos/patologia , Atrofia de Múltiplos Sistemas/patologia , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Morte Celular , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas , Atrofia de Múltiplos Sistemas/metabolismo , Doença de Parkinson/metabolismo , Fenótipo , Agregados Proteicos , Agregação Patológica de Proteínas , Conformação Proteica , Proteína Desglicase DJ-1/metabolismo , Mapeamento de Interação de Proteínas , alfa-Sinucleína/química , alfa-Sinucleína/toxicidade
20.
Nucleic Acids Res ; 49(11): 6456-6473, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34107032

RESUMO

RNA-protein interactions are central to all gene expression processes and contribute to a variety of human diseases. Therapeutic approaches targeting RNA-protein interactions have shown promising effects on some diseases that are previously regarded as 'incurable'. Here, we developed a fluorescent on-bead screening platform, RNA Pull-Down COnfocal NAnoscanning (RP-CONA), to identify RNA-protein interaction modulators in eukaryotic cell extracts. Using RP-CONA, we identified small molecules that disrupt the interaction between HuR, an inhibitor of brain-enriched miR-7 biogenesis, and the conserved terminal loop of pri-miR-7-1. Importantly, miR-7's primary target is an mRNA of α-synuclein, which contributes to the aetiology of Parkinson's disease. Our method identified a natural product quercetin as a molecule able to upregulate cellular miR-7 levels and downregulate the expression of α-synuclein. This opens up new therapeutic avenues towards treatment of Parkinson's disease as well as provides a novel methodology to search for modulators of RNA-protein interaction.


Assuntos
Proteína Semelhante a ELAV 1/antagonistas & inibidores , MicroRNAs/antagonistas & inibidores , Quercetina/farmacologia , alfa-Sinucleína/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Proteína Semelhante a ELAV 1/metabolismo , Células HEK293 , Células HeLa , Humanos , MicroRNAs/metabolismo , Microscopia Confocal , RNA Mensageiro/metabolismo , alfa-Sinucleína/genética
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