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3.
Adv Exp Med Biol ; 1286: 65-76, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33725345

RESUMO

Mitochondrial bioenergetics is vital for the proper functioning of cellular compartments. Impairments in mitochondrial DNA encoding the respiratory chain complexes and other assisting proteins, accumulation of intracellular reactive oxygen species, an imbalance in cellular calcium transport, or the presence of organic pollutants, high fat-ketogenic diets or toxins, and advancing age can result in complex disorders, including cancer, metabolic disease, and neurodegenerative disorders. Such manifestations are distinctly exhibited in several age-related neurodegenerative diseases, such as in Parkinson's disease (PD). Defects in complex I along with perturbed signaling pathways is a common manifestation of PD. Impaired oxidative phosphorylation could increase the susceptibility to PD. Therefore, unraveling the mechanisms of mitochondrial complexes in clinical scenarios will assist in developing potential early biomarkers and standard tests for energy failure diagnosis and assist to pave a new path for targeted therapeutics against PD.


Assuntos
Doença de Parkinson , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Humanos , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Doença de Parkinson/genética , Doença de Parkinson/metabolismo
4.
Nat Commun ; 12(1): 1814, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753734

RESUMO

The self-assembly of α-synuclein (αS) into intraneuronal inclusion bodies is a key characteristic of Parkinson's disease. To define the nature of the species giving rise to neuronal damage, we have investigated the mechanism of action of the main αS populations that have been observed to form progressively during fibril growth. The αS fibrils release soluble prefibrillar oligomeric species with cross-ß structure and solvent-exposed hydrophobic clusters. αS prefibrillar oligomers are efficient in crossing and permeabilize neuronal membranes, causing cellular insults. Short fibrils are more neurotoxic than long fibrils due to the higher proportion of fibrillar ends, resulting in a rapid release of oligomers. The kinetics of released αS oligomers match the observed kinetics of toxicity in cellular systems. In addition to previous evidence that αS fibrils can spread in different brain areas, our in vitro results reveal that αS fibrils can also release oligomeric species responsible for an immediate dysfunction of the neurons in the vicinity of these species.


Assuntos
Amiloide/metabolismo , Corpos de Inclusão/metabolismo , Neurônios/metabolismo , alfa-Sinucleína/metabolismo , Amiloide/química , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Cinética , Microscopia Confocal , Doença de Parkinson/metabolismo , Agregação Patológica de Proteínas , Multimerização Proteica , Ratos Sprague-Dawley , alfa-Sinucleína/química
5.
Nat Commun ; 12(1): 1807, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753743

RESUMO

Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. In this study, we demonstrate that mitochondria-lysosome contacts can dynamically form in the soma, axons, and dendrites of human neurons, allowing for their bidirectional crosstalk. Parkinson's disease patient derived neurons harboring mutant GBA1 exhibited prolonged mitochondria-lysosome contacts due to defective modulation of the untethering protein TBC1D15, which mediates Rab7 GTP hydrolysis for contact untethering. This dysregulation was due to decreased GBA1 (ß-glucocerebrosidase (GCase)) lysosomal enzyme activity in patient derived neurons, and could be rescued by increasing enzyme activity with a GCase modulator. These defects resulted in disrupted mitochondrial distribution and function, and could be further rescued by TBC1D15 in Parkinson's patient derived GBA1-linked neurons. Together, our work demonstrates a potential role of mitochondria-lysosome contacts as an upstream regulator of mitochondrial function and dynamics in midbrain dopaminergic neurons in GBA1-linked Parkinson's disease.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Glucosilceramidase/genética , Lisossomos/genética , Mitocôndrias/genética , Mutação , Doença de Parkinson/genética , Células Cultivadas , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/ultraestrutura , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Glucosilceramidase/metabolismo , Humanos , Hidrólise , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Doença de Parkinson/metabolismo , Imagem com Lapso de Tempo/métodos , Proteínas rab de Ligação ao GTP/metabolismo
7.
Nat Commun ; 12(1): 1177, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608514

RESUMO

Mass spectrometry enables high-throughput screening of phosphoproteins across a broad range of biological contexts. When complemented by computational algorithms, phospho-proteomic data allows the inference of kinase activity, facilitating the identification of dysregulated kinases in various diseases including cancer, Alzheimer's disease and Parkinson's disease. To enhance the reliability of kinase activity inference, we present a network-based framework, RoKAI, that integrates various sources of functional information to capture coordinated changes in signaling. Through computational experiments, we show that phosphorylation of sites in the functional neighborhood of a kinase are significantly predictive of its activity. The incorporation of this knowledge in RoKAI consistently enhances the accuracy of kinase activity inference methods while making them more robust to missing annotations and quantifications. This enables the identification of understudied kinases and will likely lead to the development of novel kinase inhibitors for targeted therapy of many diseases. RoKAI is available as web-based tool at http://rokai.io .


Assuntos
Biologia Computacional/métodos , Redes e Vias Metabólicas , Fosfotransferases/metabolismo , Transdução de Sinais/fisiologia , Algoritmos , Doença de Alzheimer/metabolismo , Redes Reguladoras de Genes/fisiologia , Humanos , Espectrometria de Massas , Neoplasias/metabolismo , Doença de Parkinson/metabolismo , Fosfoproteínas , Fosforilação , Fosfotransferases/genética , Proteômica/métodos , Reprodutibilidade dos Testes , Software , Biologia de Sistemas/métodos
8.
Microbiome ; 9(1): 34, 2021 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-33517890

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota. RESULTS: The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice. CONCLUSIONS: Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.


Assuntos
Microbioma Gastrointestinal/fisiologia , Fármacos Neuroprotetores/farmacologia , Osteocalcina/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Propionatos/metabolismo , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Neurônios Dopaminérgicos/efeitos dos fármacos , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Infusões Parenterais , Masculino , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Osteocalcina/administração & dosagem , Oxidopamina , Doença de Parkinson/microbiologia , Doença de Parkinson/fisiopatologia , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo
9.
Medicine (Baltimore) ; 100(7): e24837, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607852

RESUMO

ABSTRACT: Dysautonomia is common in patients with Parkinson disease (PD) since disease early phase. Scales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) is a well-designed scale assessing the autonomic dysfunctions of PD patients. Our objectives were to examine the autonomic dysfunction in PD and scan without evidence of dopaminergic deficit (SWEDD) patients and to assess the correlation of autonomic dysfunctions with cerebrospinal fluid (CSF) biomarkers.An analysis of the Parkinson's Progression Markers Initiative (PPMI) data including 414 PD patients, 60 SWEDD patients, and 170 healthy controls (HCs) with baseline CSF biomarker measurements and SCOPA-AUT assessments was presented. Autonomic symptoms including gastrointestinal, urinary, cardiovascular, pupillomotor, thermoregulatory and sexual dysfunctions were assessed by SCOPA-AUT scales. Spearman correlation test was used to examine the correlations between CSF measurements and each section of SCOPA-AUT scales in HCs and subjects with PD or SWEDD.More severe autonomic dysfunctions were observed in patients with SWEDD than those with PD (P < .001). Specifically, patients with PD have lower scores on the urinary scale [4 (0-17) vs 5 (1-18)], pupillomotor scale [0 (0-3) vs 0 (0-3)], thermoregulatory scale [0 (0-4) vs 1.5 (0-10)] and sexual scale [1 (0-6) vs 2 (0-6)] compared with SWEDD patients. Thermoregulatory dysfunction scores were found correlated with CSF α-syn levels in SWEDD group, and gastrointestinal dysfunction scores were correlated with CSF Abeta1-42 in PD group. Additionally, urinary dysfunction scores were correlated with CSF total tau and tau phosphorylated at threonine 181(p-tau181) levels in both HCs and PD patients.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Dopamina/deficiência , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/líquido cefalorraquidiano , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Regulação da Temperatura Corporal/fisiologia , Estudos de Casos e Controles , Feminino , Gastroenteropatias/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/fisiopatologia , Disautonomias Primárias/etiologia , Índice de Gravidade de Doença , Inquéritos e Questionários , Doenças Urológicas/metabolismo
10.
Zhen Ci Yan Jiu ; 46(1): 21-6, 2021 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-33559421

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) on behavior, tyrosine hydroxylase (TH), mitochondrial complexes Ⅰ-Ⅳ, mitochondrial membrane potential and mitochondrial ultrastructure of Parkinson's disease (PD) mice, so as to explore its mechanism underlying improvement of PD. METHODS: C57BL/6 mice were randomly divided into normal, model, medication (Madopar) and EA groups (n=11 in each group). PD model was duplicated by intraperitoneal injection of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP, 30 mg·kg-1·d-1) for consecutively 5 d. EA was performed on the chorea tremor areas on both sides of the head of mice for 15 min, once a day for 14 d. The behavioral changes of mice were observed. The expression of TH in substantia nigra compacta of midbrain was detected by immunohistochemistry. The activities of mitochondrial complexes Ⅰ-Ⅳ were measured. The changes of mitochondrial membrane potential were detected by JC-1 staining method. The ultrastructural changes of striatum mitochondria were observed by transmission electron microscope. RESULTS: After modeling, the mice showed obvious behavioral abnormalities such as tremor, vertical hair and tail warping, and the pole test time in the model group was significantly longer than that in the normal group (P<0.01). After 7 and 14 days of the treatment, the pole test time in the EA and medication groups was shorter than that in the model group (P<0.05,P<0.01). Compared with the normal group, the number of TH positive cells of the substantia nigra, the mitochondrial membrane potential and the activity of mitochondrial complex I were decreased significantly in the model group (P<0.01), and EA and medication intervention reversed these changes (P<0.01). The mitochondrial structure of mice in the model group was obviously damaged, and the damage of mitochondrial structure was alleviated and the number of damaged mitochondria was decreased in the EA and medication groups. CONCLUSION: EA can protect and promote the recovery of mitochondrial structure and function in MPTP-induced PD mice, which may play a neuroprotective effect on PD mice by improving mitochondrial dysfunction, balancing cell homeostasis and reducing dopaminergic neuron damage.


Assuntos
Eletroacupuntura , Doença de Parkinson , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Substância Negra/metabolismo
11.
Methods Mol Biol ; 2224: 75-85, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606207

RESUMO

Parkinson's disease is a neurodegenerative disorder characterized by accumulation of misfolded α-synuclein within the central nervous system (CNS). Retinal manifestations have been widely described as a prodromal symptom; however, we have a limited understanding of the retinal pathology associated with Parkinson's disease. The strong similarities between the retina and the brain and the accessibility of the retina has potentiated studies to investigate retinal pathology in an effort to identify biomarkers for early detection, as well as for monitoring the progression of disease and efficacy of therapies as they become available. Here, we discuss a study conducted using a transgenic mouse model of Parkinson's disease (TgM83, expressing human α-synuclein containing the familial PD-associated A53T mutation) to demonstrate the effect of the A53T α-synuclein mutation on the retina. Additionally, we show that "seeding" with brain homogenates from clinically ill TgM83 mice accelerates the accumulation of retinal α-synuclein. The work described in this chapter provides insight into retinal changes associated with Parkinson's disease and identifies retinal indicators of Parkinson's disease pathogenesis that could serve as potential biomarkers for early detection.


Assuntos
Doença de Parkinson/metabolismo , Retina/metabolismo , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Doença de Parkinson/genética , alfa-Sinucleína/genética
12.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466734

RESUMO

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson's disease, Tourette's syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.


Assuntos
Canabinoides/farmacologia , Cannabis/química , Descoberta de Drogas , Compostos Fitoquímicos/farmacologia , Terpenos/farmacologia , Animais , Canabinoides/química , Canabinoides/uso terapêutico , Sinergismo Farmacológico , Endocanabinoides/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico , Receptores de Canabinoides/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Terpenos/química , Terpenos/uso terapêutico , Síndrome de Tourette/tratamento farmacológico , Síndrome de Tourette/metabolismo
13.
Nat Chem Biol ; 17(3): 237-245, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33432239

RESUMO

Amyloid aggregation, which disrupts protein homeostasis, is a common pathological event occurring in human neurodegenerative diseases (NDs). Numerous evidences have shown that the structural diversity, so-called polymorphism, is decisive to the amyloid pathology and is closely associated with the onset, progression, and phenotype of ND. But how could one protein form so many stable structures? Recently, atomic structural evidence has been rapidly mounting to depict the involvement of chemical modifications in the amyloid fibril formation. In this Perspective, we aim to present a hierarchical regulation of chemical modifications including covalent post-translational modifications (PTMs) and noncovalent cofactor binding in governing the polymorphic amyloid formation, based mainly on the latest α-synuclein and Tau fibril structures. We hope to emphasize the determinant role of chemical modifications in amyloid assembly and pathology and to evoke chemical biological approaches to lead the fundamental and therapeutic research on protein amyloid state and the associated NDs.


Assuntos
Amiloide/química , Proteínas de Ligação a DNA/química , Processamento de Proteína Pós-Traducional , alfa-Sinucleína/química , Proteínas tau/química , Acetilação , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Modelos Moleculares , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fosforilação , Poli Adenosina Difosfato Ribose/química , Poli Adenosina Difosfato Ribose/metabolismo , Agregados Proteicos , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
14.
Biomed Pharmacother ; 134: 111170, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33383311

RESUMO

Huang Lian Jie Du Tang (HLJDT) is a traditional Chinese medical decoction for heat-fire clearing and detoxication. Theoretically, the cause of Parkinson's disease (PD) has been attributed to the dysregulations of internal wind, phlegm, fire, and stasis. Thus, HLJDT has been used to treat PD. However, the molecular mechanism is unknown. Besides, paraquat (PQ) as an herbicide has been known to impair midbrain dopaminergic neurons, resemblance to the pathology of PD. Thus, the molecular mechanism of HLJDT in treating PD and PQ-induced in vitro PD model was investigated in this study. Primarily, the dose-response of PQ (0.1∼1 mM)-induced neurotoxicity for 24 h was performed in the human neuroblastoma SH-SY5Y cells. The LD50 of PQ is around 0.3 mM and was applied throughout the following experiments. The neutral red assay was used to estimate cell viability. Co-transfection of the mitochondrial marker and proapoptotic factor genes were applied to measure the release of mitochondrial proapoptotic factors during PQ intoxication and HLJDT protection. The fluorescent dyes were used to detect mitochondrial membrane potential and free radical formation. Western blot and dot-blot analysis and immunocytochemistry were used to estimate the level of proteins related to apoptosis and mitophagy. PINK1 gene silencing was used to determine the significance of mitophagy during PQ intoxication. In this study, HLJDT attenuated PQ-induced apoptosis in SH-SY5Y cells. HLJDT reversed PQ-induced decreased mitochondrial membrane potential and suppressed PQ-induced increased cytosolic and mitochondrial free radical formations and mitochondrial proapoptotic factor releases. Furthermore, HLJDT mitigated PQ-induced increases in full-length PINK1, phosphorylations of Parkin and ubiquitin, mitochondrial translocation of phosphorylated Parkin, and mitophagy. PINK1 gene silencing attenuated PQ-induced neurotoxicity. Therefore, HLJDT attenuated PQ-induced cell death by regulating mitophagy.


Assuntos
Antiparkinsonianos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Paraquat/toxicidade , Doença de Parkinson/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fosforilação , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
15.
Phytomedicine ; 80: 153369, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33070082

RESUMO

BACKGROUND: Impairment of mitochondrial biogenesis is associated with the pathological progression of Parkinson's disease (PD). Parkin-interacting substrate (PARIS) can be ubiquitinated by parkin and prevents the repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α). PURPOSE: This study investigated whether the neuroprotective mechanism of carnosic acid (CA) from rosemary is mediated via the regulation of PARIS and PGC-1α by parkin. METHODS: The Western blotting and RT-PCR were used to determine protein and mRNA, respectively. To investigate the protein-protein interaction of between PARIS and ubiquitin, the immunoprecipitation assay (IP assay) was utilized. Silencing of endogenous parkin or PGC-1α was performed by using transient transfection of small interfering RNA (siRNA). RESULTS: SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA) increased PARIS protein, decreased PGC-1α protein, and reduced protein and mRNA of mitochondrial biogenesis-related genes. CA pretreatment reversed the effects of 6-OHDA. By IP assay, the interaction of PARIS with ubiquitin protein caused by CA was stronger than that caused by 6-OHDA. Moreover, knockdown of parkin attenuated the ability of CA to reverse the 6-OHDA-induced increase in PARIS and decrease in PGC-1α expression. PGC-1α siRNA was used to investigate how CA influenced the effect of 6-OHDA on the modulation of mitochondrial biogenesis and apoptosis. In the presence of PGC-1α siRNA, CA could no longer significantly reverse the reduction of mitochondrial biogenesis or the induction of cleavage of apoptotic-related proteins by 6-OHDA. CONCLUSION: The cytoprotective of CA is related to the enhancement of mitochondrial biogenesis by inhibiting PARIS and inducing PGC-1α by parkin. The activation of PGC-1α-mediated mitochondrial biogenesis by CA prevents the degeneration of dopaminergic neurons, CA may have therapeutic application in PD.


Assuntos
Abietanos/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Repressoras/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Biogênese de Organelas , Oxidopamina/toxicidade , Doença de Parkinson/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , RNA Interferente Pequeno/farmacologia , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
16.
Clin Nucl Med ; 46(2): 119-124, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33323728

RESUMO

INTRODUCTION: Degeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [18F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter. Here we describe our initial experience with [18F]PR04.MZ PET/CT in a larger cohort of healthy controls and PD patients as a proof-of-concept study for this tracer. METHODS: Eighteen healthy subjects, 19 early PD patients (Hoehn-Yahr I-II), and 13 moderate-advanced PD patients (Hoehn-Yahr III-IV) underwent static PET/CT scans 60 to 90 minutes after injection of 5.16 ± 1.03 mCi (191 ± 38 MBq) [18F]PR04.MZ. Specific binding ratios (SBRs) were calculated for caudate nucleus, anterior putamen, posterior putamen, substantia nigra (SNpc), compared between different groups and correlated with clinical ratings. RESULTS: [18F]PR04.MZ showed very high and specific uptake in the putamen, caudate, and substantia nigra pars compacta and very low nonspecific binding in other brain regions, and SBR values for the control group were 22.3 ± 4.1, 19.1 ± 3.5, and 5.4 ± 1.2, respectively. A reduction of SBR values was observed in all regions and in both initial and moderate PD, ranging from 35% to 89% (P < 0.001). The observed pattern of reduction was posterior putamen > anterior putamen > substantia nigra pars compacta > caudate, with contralateral posterior putamen being the most affected region. Rostrocaudal depletion gradient was evident in all PD patients and progression correlated with motor manifestations. CONCLUSIONS: [18F]PR04.MZ PET/CT is a highly sensitive imaging modality for the detection of dopaminergic deficit in nigrostriatal pathways in PD.


Assuntos
Neurônios/patologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Substância Negra/patologia , Idoso , Estudos de Coortes , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Doença de Parkinson/metabolismo
17.
Carbohydr Polym ; 254: 117435, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33357908

RESUMO

Parkinson's disease (PD) develops due to oxidative stress, mitochondrial aberrations, posttranslational modification, and α-Synuclein (α-Syn) aggregation. The α-synucleinopathy is attributed to phosphorylation and aggregation of α-Syn. A strategy to degrade or reduce phosphorylated protein paves the way to develop PD therapy. Hence, the neuroprotective efficiency of PP2A (Protein phosphatase 2) activator FTY720, loaded chitosan nanoformulation has been evaluated in vitro and ex vivo experimental PD models. Bio-compatible chitosan-based nanocarriers have been utilized to enhance the bio-availability and neuroprotective effect of FTY720. The neuroprotective effect of characterized nanoformulation was determined by the downregulation of PD hallmark phospho-serine 129 (pSer129) α-Syn, with anti-oxidative and anti-inflammatory potentials. The neuroprotective mechanism uncovered novel physical interaction of PP2A and polycomb group of protein Enhancer of zeste homolog 2 to mediate ubiquitination and degradation of agglomerated pSer129 α-Syn. Indeed, this study establishes the neuroprotective potential of chitosan based FTY720 nanoformulations by PP2A mediated epigenetic regulation for PD prevention.


Assuntos
Quitosana/química , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Cloridrato de Fingolimode/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Proteína Fosfatase 2/genética , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Modelos Animais de Doenças , Portadores de Fármacos/química , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Cloridrato de Fingolimode/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacocinética , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fosforilação/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Proteólise/efeitos dos fármacos , Transdução de Sinais , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacocinética , Ubiquitinação/efeitos dos fármacos , alfa-Sinucleína/química , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
18.
Int J Mol Sci ; 21(24)2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33327559

RESUMO

Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by a progressive degeneration of the central or peripheral nervous systems. A central role of the RNA metabolism has emerged in these diseases, concerning mRNAs processing and non-coding RNAs biogenesis. We aimed to identify possible common grounds or differences in the dysregulated pathways of AD, PD, and ALS. To do so, we performed RNA-seq analysis to investigate the deregulation of both coding and long non-coding RNAs (lncRNAs) in ALS, AD, and PD patients and controls (CTRL) in peripheral blood mononuclear cells (PBMCs). A total of 293 differentially expressed (DE) lncRNAs and 87 mRNAs were found in ALS patients. In AD patients a total of 23 DE genes emerged, 19 protein coding genes and four lncRNAs. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses, we found common affected pathways and biological processes in ALS and AD. In PD patients only five genes were found to be DE. Our data brought to light the importance of lncRNAs and mRNAs regulation in three principal neurodegenerative disorders, offering starting points for new investigations on deregulated pathogenic mechanisms.


Assuntos
Doença de Alzheimer/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/genética , Esclerose Amiotrófica Lateral/genética , Humanos , Doença de Parkinson/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , RNA-Seq
19.
PLoS Comput Biol ; 16(12): e1008503, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33347433

RESUMO

In this work, we introduce new phenomenological neuronal models (eLIF and mAdExp) that account for energy supply and demand in the cell as well as the inactivation of spike generation how these interact with subthreshold and spiking dynamics. Including these constraints, the new models reproduce a broad range of biologically-relevant behaviors that are identified to be crucial in many neurological disorders, but were not captured by commonly used phenomenological models. Because of their low dimensionality eLIF and mAdExp open the possibility of future large-scale simulations for more realistic studies of brain circuits involved in neuronal disorders. The new models enable both more accurate modeling and the possibility to study energy-associated disorders over the whole time-course of disease progression instead of only comparing the initially healthy status with the final diseased state. These models, therefore, provide new theoretical and computational methods to assess the opportunities of early diagnostics and the potential of energy-centered approaches to improve therapies.


Assuntos
Potenciais de Ação/fisiologia , Metabolismo Energético , Modelos Neurológicos , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Humanos , Rede Nervosa , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Convulsões/metabolismo , Convulsões/fisiopatologia , ATPase Trocadora de Sódio-Potássio/metabolismo
20.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333772

RESUMO

Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named "non-neuronal cells." In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells-and therefore the control of neuroinflammation-depends on the local "on demand" synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide-either by decreasing its degradation or exogenous administration-is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.


Assuntos
Amidas/administração & dosagem , Amidas/metabolismo , Etanolaminas/administração & dosagem , Etanolaminas/metabolismo , Inflamação/dietoterapia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Ácidos Palmíticos/administração & dosagem , Ácidos Palmíticos/metabolismo , Doença de Alzheimer/dietoterapia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Esclerose Amiotrófica Lateral/dietoterapia , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/metabolismo , Animais , Transtorno do Espectro Autista/dietoterapia , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Endocanabinoides/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Redes e Vias Metabólicas , Esclerose Múltipla/dietoterapia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Doenças do Sistema Nervoso/dietoterapia , Doenças do Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/dietoterapia , Doenças Neurodegenerativas/metabolismo , Dor/dietoterapia , Dor/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo
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