RESUMO
Parkinson's disease (PD) is a neurodegenerative disorder affecting 2-3% of those aged over 65, characterized by motor symptoms like slow movement, tremors, and muscle rigidity, along with non-motor symptoms such as anxiety and dementia. Lewy bodies, clumps of misfolded proteins, contribute to neuron loss in PD. Mutations in the GBA1 gene are considered the primary genetic risk factor of PD. GBA1 mutations result in decreased activity of the lysosomal enzyme glucocerebrosidase (GCase) resulting in α-synuclein accumulation. We know that α-synuclein aggregation, lysosomal dysfunction, and endoplasmic reticulum disturbance are recognized factors to PD susceptibility; however, the molecular mechanisms connecting GBA1 gene mutations to increased PD risk remain partly unknown. Thus, in this narrative review conducted according to a systematic review method, we aimed to present the main contributions arising from the molecular impact of the GBA1 gene to the pathogenesis of PD providing new insights into potential impacts for advances in the clinical care of people with PD, a neurological disorder that has contributed to the substantial increase in the global burden of disease accentuated by the aging population. In summary, this narrative review highlights the multifaceted impact of GBA1 mutations in PD, exploring their role in clinical manifestations, genetic predispositions, and molecular mechanisms. The review emphasizes the importance of GBA1 mutations in both motor and non-motor symptoms of PD, suggesting broader therapeutic and management strategies. It also discusses the potential of CRISPR/Cas9 technology in advancing PD treatment and the need for future research to integrate these diverse aspects for improved diagnostics and therapies.
Assuntos
Glucosilceramidase , Mutação , Doença de Parkinson , Humanos , Glucosilceramidase/genética , Doença de Parkinson/genética , Doença de Parkinson/enzimologia , Mutação/genética , Animais , Predisposição Genética para Doença , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
BACKGROUND: Drugs used for Parkinson's disease (PD) are mainly responsible for only relieving major symptoms, but may present several side effects that are typical of such pharmacological treatment. METHODS: This study aimed to use in silico methods for drug designing inhibitors of the PD therapeutic target, monoamine oxidase B (MAO-B). Thus, 20 MAO-B inhibitors from the BindingDB database were selected followed by a calculation of their descriptors at DFT B3LYP/6-31G** level of theory. RESULTS: Statistical analysis considering a Pearson correlation matrix led to the selection of electrophilicity index as a descriptor related to the biological activity of inhibitors. Furthermore, based on the prediction of suitable ADME/Tox properties, the molecule CID 54583085 was selected as a template to carry out structural modifications to obtain 3 analogues, whereas molecules B and C showed significant improvement in mutagenicity and carcinogenicity, in relation to the template. CONCLUSION: Thus, it is concluded that the proposed modifications led us to satisfactory results, since there was an improvement in the toxicological properties of molecules, however, further studies must be carried out to evaluate their biological activities as possible MAO-B inhibitors for PD treatment.
Assuntos
Antiparkinsonianos/química , Desenho de Fármacos , Inibidores da Monoaminoxidase/química , Monoaminoxidase/metabolismo , Doença de Parkinson/enzimologia , Antiparkinsonianos/uso terapêutico , Humanos , Inibidores da Monoaminoxidase/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Eletricidade Estática , Resultado do TratamentoRESUMO
Mitochondrial dysfunction, a common factor in several diseases is accompanied with reactive oxygen species (ROS) production. These molecules react with proteins and lipids at their site of generation, establishing a vicious cycle which might result in further mitochondrial injury. It is well established that mitochondrial respiratory complexes can be organized into supramolecular structures called supercomplexes (SCs) or respirasomes; yet, the physiological/pathological relevance of these structures remains unresolved. Changes in their stabilization and content have been documented in Barth's syndrome, degenerative diseases such as Parkinson's and Alzheimer, cardiovascular diseases including heart failure and ischemia-reperfusion damage, as well as in aging. Under pathological conditions, SCs stability could have relevant biomedical implications or might be used as a reliable marker of mitochondrial damage. The purpose of this review is to recapitulate the current state of the significance on mitochondrial bioenergetics of these structures and their possible role in pathophysiologies related with ROS increase.
Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/enzimologia , Síndrome de Barth/enzimologia , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/enzimologia , Membranas Mitocondriais/metabolismo , Doença de Parkinson/enzimologia , Envelhecimento/patologia , Doença de Alzheimer/patologia , Animais , Síndrome de Barth/patologia , Metabolismo Energético , Humanos , Membranas Mitocondriais/patologia , Doença de Parkinson/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
The most commonly used Parkinson's disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l-dopa). Monoamine oxidase-B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single-nucleotide polymorphisms (SNPs) in the MAO-B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (l-dopa). A total of 162 Brazilian patients from the Pro-Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled. PD patients were stratified into 2 groups according to the daily levodopa dose. MAO-B and COMT SNP genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism. After multivariate analysis, we observed a significant difference between PD groups for the following variables: sex (P = .02), longer duration of disease (P = .02), longer levodopa therapy duration (P = .01), younger onset of PD (P = .01), and use of COMT inhibitor (P = .02). We observed that patients carrying MAO-B (rs1799836) A and AA genotypes and COMT (rs4680) LL genotype suffered more frequently from levodopa-induced-dyskinesia. In addition, we found an increased risk of 2.84-fold for male individuals carrying the MAO-B G allele to be treated with higher doses of levodopa (P = .04). We concluded that before beginning PD pharmacological treatment, it is important to consider the genetic variants of the MAO-B and COMT genes and the sex, reinforcing the evidence that sexual dimorphism in the genes related to dopamine metabolism might affect PD treatment.
Assuntos
Antiparkinsonianos/administração & dosagem , Catecol O-Metiltransferase/genética , Levodopa/administração & dosagem , Monoaminoxidase/genética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Adulto , Idoso , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapêutico , Disponibilidade Biológica , Brasil , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Discinesias , Feminino , Genótipo , Humanos , Levodopa/efeitos adversos , Levodopa/farmacocinética , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/enzimologia , Variantes Farmacogenômicos/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Caracteres Sexuais , Inquéritos e QuestionáriosRESUMO
Dopamine replacement therapy with L-DOPA is the treatment of choice for Parkinson's disease; however, its long-term use is frequently associated with L-DOPA-induced dyskinesia (LID). Many molecules have been implicated in the development of LID, and several of these have been proposed as potential therapeutic targets. However, to date, none of these molecules have demonstrated full clinical efficacy, either because they lie downstream of dopaminergic signaling, or due to adverse side effects. Therefore, discovering new strategies to reduce LID in Parkinson's disease remains a major challenge. Here, we have explored the tyrosine kinase Fyn, as a novel intermediate molecule in the development of LID. Fyn, a member of the Src kinase family, is located in the postsynaptic density, where it regulates phosphorylation of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in response to dopamine D1 receptor stimulation. We have used Fyn knockout and wild-type mice, lesioned with 6-hydroxydopamine and chronically treated with L-DOPA, to investigate the role of Fyn in the induction of LID. We found that mice lacking Fyn displayed reduced LID, ΔFosB accumulation and NR2B phosphorylation compared to wild-type control mice. Pre-administration of saracatinib (AZD0530), an inhibitor of Fyn activity, also significantly reduced LID in dyskinetic wild-type mice. These results support that Fyn has a critical role in the molecular pathways affected during the development of LID and identify Fyn as a novel potential therapeutic target for the management of dyskinesia in Parkinson's disease.
Assuntos
Discinesia Induzida por Medicamentos/complicações , Discinesia Induzida por Medicamentos/enzimologia , Doença de Parkinson/complicações , Doença de Parkinson/enzimologia , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Animais , Benzodioxóis/farmacologia , Discinesia Induzida por Medicamentos/patologia , Discinesia Induzida por Medicamentos/fisiopatologia , Feminino , Levodopa , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Movimento , Neostriado/metabolismo , Neostriado/patologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Fosforilação , Subunidades Proteicas/metabolismo , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , Quinazolinas/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Myeloperoxidase (MPO) is an inducible heme peroxidase responsive to some stress situations. It is already known that its activity is stimulated in neurodegenerative disorders and in the animal model of parkinson's disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). By contrast, the role of δ-aminolevulinate dehydratase (δ-ALA-D), an essential enzyme for heme synthesis, has not been investigated in the MPTP model. The aim of this study was to investigate the involvement of striatal δ-ALA-D activity in an acute model of PD, induced by MPTP, in C57Bl/6 mice and its correlation with MPO activity. Animals received four MPTP injections (20 mg/kg, i.p.) or saline (vehicle) to induce a PD model. 7 days after MPTP administration, the motor function was evaluated through rotarod and challenging beam tests in mice. Afterward, mice were killed, and the striata were removed for biochemical analyses. MPTP-treated mice showed impairment in motor skills, such as balance and motor coordination. Furthermore, there was a reduction of tyrosine hydroxylase levels in these animals, which characterizes the dopaminergic lesion. Striatal δ-ALA-D activity was stimulated by MPTP, as well as the MPO activity, and a significant positive correlation between δ-ALA-D and MPO activities was also demonstrated. These data suggest that δ-ALA-D activity could be stimulated due to the requirement of heme groups by peroxidases. Therefore, this study demonstrated for the first time the involvement of striatal δ-ALA-D activity in the MPTP model and its correlation with the MPO activity.
Assuntos
Doença de Parkinson/enzimologia , Peroxidase/metabolismo , Sintase do Porfobilinogênio/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doença de Parkinson/patologiaRESUMO
Mutations the in human DJ-1 (hDJ-1) gene are associated with early-onset autosomal recessive forms of Parkinson's disease (PD). hDJ-1/parkinsonism associated deglycase (PARK7) is a cytoprotective multi-functional protein that contains a conserved cysteine-protease domain. Given that cysteine-proteases can act on both amide and ester substrates, we surmised that hDJ-1 possessed cysteine-mediated esterase activity. To test this hypothesis, hDJ-1 was overexpressed, purified and tested for activity towards 4-nitrophenyl acetate (pNPA) as µmol of pNPA hydrolyzed/min/mg·protein (U/mg protein). hDJ-1 showed maximum reaction velocity esterase activity (Vmax = 235.10 ± 12.00 U/mg protein), with a sigmoidal fit (S0.5 = 0.55 ± 0.040 mM) and apparent positive cooperativity (Hill coefficient of 2.05 ± 0.28). A PD-associated mutant of DJ-1 (M26I) lacked activity. Unlike its protease activity which is inactivated by reactive oxygen species (ROS), esterase activity of hDJ-1 is enhanced upon exposure to low concentrations of hydrogen peroxide (<10 µM) and plateaus at elevated concentrations (>100 µM) suggesting that its activity is resistant to oxidative stress. Esterase activity of DJ-1 requires oxidation of catalytic cysteines, as chemically protecting cysteines blocked its activity whereas an oxido-mimetic mutant of DJ-1 (C106D) exhibited robust esterase activity. Molecular docking studies suggest that C106 and L126 within its catalytic site interact with esterase substrates. Overall, our data show that hDJ-1 contains intrinsic redox-sensitive esterase activity that is abolished in a PD-associated mutant form of the hDJ-1 protein.
Assuntos
Esterases/química , Esterases/metabolismo , Doença de Parkinson/enzimologia , Esterases/genética , Humanos , Peróxido de Hidrogênio/farmacologia , Simulação de Acoplamento Molecular , Mutação , Nitrofenóis/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/genética , Proteína Desglicase DJ-1/química , Proteína Desglicase DJ-1/genética , Proteína Desglicase DJ-1/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Although various individual studies have evaluated the correlation between monoamine oxidase B (MAOB), polymorphism, and Parkinson's disease (PD), the results remain inconclusive. Therefore, we performed a meta-analysis in the Chinese population to provide comprehensive data on the association between the MAOB polymorphism and PD. Eligible studies were identified via databases such as PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine, throughout November 2015. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strengths of these associations. Eight studies documenting a total of 1385 cases of PD and 1426 controls were included in this meta-analysis. Overall, no significant association was found between the MAOB A644G polymorphism and PD risk in the Chinese population. However, in subgroup analyses, where results were stratified by geographical areas and source of controls, increased risk for PD in Northern China was observed (allele A vs G: OR = 1.33, 95%CI = 1.11-1.58; AA vs GG: OR = 1.46, 95%CI = 1.09-1.97; AA + AG vs GG: OR = 1.42, 95%CI = 1.06-1.90). Similarly, population-based studies also showed significant association between the MAOB A644G polymorphism and PD risk among different populations (allele A vs G: OR = 1.29, 95%CI = 1.11-1.51; AA vs GG: OR = 1.41, 95%CI = 1.09-1.82; AA + AG vs GG: OR = 1.34, 95%CI = 1.04- 1.71). In conclusion, this meta-analysis provided evidence that the MAOB A644G polymorphism may contribute to PD development in Northern China. Further studies conducted in other ethnic groups are required for definite conclusions.
Assuntos
Povo Asiático/genética , Monoaminoxidase/genética , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Alelos , Estudos de Casos e Controles , China , Predisposição Genética para Doença , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
The most significant pathological feature of Parkinson's disease (PD) is the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra. Currently, available treatments for PD cannot prevent the loss of DA neurons. Tyrosine hydroxylase (TH) expressed in substantia nigra neurons catalyzes the conversion of tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the rate-limiting step of DA biosynthesis. Major reasons for PD occurrence include decreased TH activity in the substantia nigra and secondary DA suppression. Decreased TH activity and the resulting suppression of DA synthesis (or neurotransmission) in the substantia nigra are key factors underlying the development of PD. Cellular prion protein (PRP) is a membrane glycoprotein expressed in the central nervous system. Although the sequence of PRP is highly conserved, its physiological function is unclear. The purpose of this study was to investigate the effect of PRP-targeted small interfering RNA (siRNA) on TH expression in a rat model of PD. Thirty male Wistar rats were injected with 6-hydroxydopamine (6-OHDA) to generate a model of PD. The rats then received injections of PRP-siRNA or nonsense siRNA in the lateral ventricles. Substantia nigra samples were collected for quantification of PRP and TH expression using real-time polymerase chain reaction and western blotting. PRP-siRNA decreased PRP expression in the substantia nigra. TH expression was decreased in PD model rats but was increased after PRP silencing. We conclude that PRP-siRNA may increase TH expression in vivo and may therefore exert protective effects on neurons in a model of PD.
Assuntos
Doença de Parkinson/metabolismo , Proteínas Priônicas/genética , RNA Interferente Pequeno/administração & dosagem , Substância Negra/fisiologia , Tirosina 3-Mono-Oxigenase/biossíntese , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Inativação Gênica , Masculino , Modelos Animais , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Proteínas Priônicas/fisiologia , RNA Interferente Pequeno/genética , Ratos , Ratos Wistar , Substância Negra/enzimologia , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Genetic and environmental factors affect the pathogenesis of Parkinson's disease (PD). Genetic variants of the enzyme glutathione S-transferases (GST) may be related to the disease. This study aimed to evaluate the influence of genetic variants of GST (GSTT1/GSTM1) and their association with the exposure to environmental toxins in PD patients. We studied 254 patients with PD and 169 controls. The GSTM1/GSTT1 variants were analyzed by polymerase chain reaction. We applied the Fisher's exact test and the χ2 test for statistical analysis (p<0.05). The present and absence for GSTT1 and GSTM1 were similar in patients and controls. The null for GSTT1 and GSTM1 (0/0) and exposure to pesticides prevailed in patients (18%) compared to controls (13%, p=0.014). This study suggests the association between PD and previous exposure to pesticides, whose effect may be enhanced in combination with null for GSTT1/GSTM1.