ABSTRACT
This study aims to explore the neuroprotective mechanism of ginsenoside Re(GS-Re) on drosophila model of Parkinson's disease(PD) induced by rotenone(Rot). To be specific, Rot was used to induce PD in drosophilas. Then the drosophilas were grouped and respectively treated(GS-Re: 0.1, 0.4, 1.6 mmol·L~(-1); L-dopa: 80 μmol·L~(-1)). Life span and crawling ability of drosophilas were determined. The brain antioxidant activity [content of catalase(CAT), malondialdehyde(MDA), reactive oxygen species(ROS), superoxide dismutase(SOD)], dopamine(DA) content, and mitochondrial function [content of adenosine triphosphate(ATP), NADH:ubiquinone oxidoreductase subunit B8(NDUFB8) Ⅰ activity, succinate dehydrogenase complex, subunit B(SDHB) Ⅱ activity] were detected by enzyme-linked immunosorbent assay(ELISA). The number of DA neurons in the brains of drosophilas was measured with the immunofluorescence method. The levels of NDUFB8 Ⅰ, SDHB Ⅱ, cytochrome C(Cyt C), nuclear factor-E2-related factor 2(Nrf2), heme oxygenase-1(HO-1), B-cell lymphoma/leukemia 2(Bcl-2)/Bcl-2-assaciated X protein(Bax), and cleaved caspase-3/caspase-3 in the brain were detected by Western blot. The results showed that model group [475 μmol·L~(-1) Rot(IC_(50))] demonstrated significantly low survival rate, obvious dyskinesia, small number of neurons and low DA content in the brain, high ROS level and MDA content, low content of SOD and CAT, significantly low ATP content, NDUFB8 Ⅰ activity, and SDHB Ⅱ activity, significantly low expression of NDUFB8 Ⅰ, SDHB Ⅱ, and Bcl-2/Bax, large amount of Cyt C released from mitochondria to cytoplasm, low nuclear transfer of Nrf2, and significantly high expression of cleaved caspase-3/caspase-3 compared with the control group. GS-Re(0.1, 0.4, and 1.6 mmol·L~(-1)) significantly improved the survival rate of PD drosophilas, alleviated the dyskinesia, increased DA content, reduced the loss of DA neurons, ROS level, and MDA content in brain, improved content of SOD and CAT and antioxidant activity in brain, maintained mitochondrial homeostasis(significantly increased ATP content and activity of NDUFB8 Ⅰ and SDHB Ⅱ, significantly up-regulated expression of NDUFB8 Ⅰ, SDHB Ⅱ, and Bcl-2/Bax), significantly reduced the expression of Cyt C, increased the nuclear transfer of Nrf2, and down-regulated the expression of cleaved caspase-3/caspase-3. In conclusion, GS-Re can significantly relieve the Rot-induced cerebral neurotoxicity in drosophilas. The mechanism may be that GS-Re activates Keap1-Nrf2-ARE signaling pathway by maintaining mitochondrial homeostasis, improves antioxidant capacity of brain neurons, then inhibits mitochondria-mediated caspase-3 signaling pathway, and the apoptosis of neuronal cells, thereby exerting the neuroprotective effect.
Subject(s)
Animals , Reactive Oxygen Species/metabolism , Antioxidants/pharmacology , Oxidative Stress , NF-E2-Related Factor 2/metabolism , Caspase 3/metabolism , Parkinson Disease/genetics , bcl-2-Associated X Protein/metabolism , Neuroprotective Agents/pharmacology , Kelch-Like ECH-Associated Protein 1/metabolism , Drosophila/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Apoptosis , Superoxide Dismutase/metabolism , Adenosine Triphosphate/pharmacologyABSTRACT
BACKGROUNDS: Parkinson's disease (PD) is a common age-related neurodegenerative disorder worldwide. This research aimed to investigate the effects and mechanism underlying long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in PD. METHODS: SK-N-SH and SK-N-BE cells were treated with MPP+ to establish the MPP+-stimulated cell model of PD, and MALAT1 expression was determined. Then, the effects of MALAT1 depletion on cell proliferation and apoptosis were determined in the MPP+-stimulated cell model of PD. Besides, the correlations between microRNA-135b-5p (miR-135b-5p) and MALAT1 or glycoprotein nonmetastatic melanoma protein B (GPNMB) in MPP+-stimulated cell model of PD were explored. RESULTS: MALAT1 was increasingly expressed and downregulation of MALAT1 promoted cell proliferation while inhibited apoptosis in MPP+-stimulated cells. Besides, miR-135b-5p was a target of MALAT1 and directly targeted to GPNMB. Further investigation indicated that suppression of MALAT1 regulated cell proliferation and apoptosis by miR-135b-5p/GPNMB axis. CONCLUSION: Our findings reveal that MALAT1/miR-135b-5p/GPNMB axis regulated cell proliferation and apoptosis in MPP+-stimulated cell model of PD, providing a potential biomarker and therapeutic target for PD.
Subject(s)
Humans , Parkinson Disease/genetics , Membrane Glycoproteins/genetics , Apoptosis , MicroRNAs/genetics , Cell Proliferation , RNA, Long Noncoding/genetics , Cells, CulturedABSTRACT
In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington's disease. In the brain of Alzheimer's disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer's disease and Parkinson's disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.
Subject(s)
Animals , Humans , DNA Methylation , Epigenesis, Genetic , Neurodegenerative Diseases/genetics , Parkinson Disease/genetics , Protein Processing, Post-TranslationalABSTRACT
BACKGROUND: Long non-coding RNA small molecule RNA host gene 1 (SNHG1) was previously identified to be relevant with Parkinson's disease (PD) pathogenesis. This work aims to further elucidate the regulatory networks of SNHG1 involved in PD. Methods: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-hydrochloride (MPTP)-induced mice and 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells were respectively constructed as the in vivo and in vitro PD models. Expression levels of SNHG1 and miR-153-3p were detected by qRT-PCR. Protein expression levels of phosphate and tension homology deleted on chromosome ten (PTEN) were measured by western blotting assay. Cell viability and apoptosis were determined by MTT and flow cytometry assays. The interactions among SNHG1, miR-153-3p and PTEN were identified by luciferase reporter assay, RNA immunoprecipitation, and/or RNA pull-down analysis. RESULTS: Increased SNHG1 expression was found in midbrain of MPTP-induced PD mice and MPP+-treated SH-SY5Y cells. Overexpression of SNHG1 lowered viability and enhanced apoptosis in MPP+-treated SH-SY5Y cells. Moreover, SNHG1 acted as a molecular sponge to inhibit the expression of miR-153-3p. Furthermore, miR-153-3p-mediated suppression of MPP+-induced cytotoxicity was abated following SNHG1 up-regulation. Additionally, PTEN was identified as a direct target of miR-153-3p, and SNHG1 could serve as a competing endogenous RNA (ceRNA) of miR-153-3p to improve the expression of PTEN. Besides, enforced expression of PTEN displayed the similar functions as SNHG1 overexpression in regulating the viability and apoptosis of MPP+-treated SH-SY5Y cells. Finally, SNHG1 was found to activate PTEN/AKT/mTOR signaling pathway in SH-SY5Y cells by targeting miR-153-3p. CONCLUSION: SNHG1 aggravates MPP+-induced cellular toxicity in SH-SY5Y cells by regulating PTEN/AKT/mTOR signaling via sponging miR-153-3p, indicating the potential of SNHG1 as a promising therapeutic target for PD.
Subject(s)
Animals , Male , Mice , Parkinson Disease/metabolism , 1-Methyl-4-phenylpyridinium/toxicity , PTEN Phosphohydrolase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , RNA, Long Noncoding/metabolism , Parkinson Disease/genetics , Transfection , Signal Transduction , Cells, Cultured , Gene Expression Regulation , Blotting, Western , Apoptosis , MicroRNAs , Disease Models, Animal , Real-Time Polymerase Chain Reaction , RNA, Long Noncoding/genetics , Mice, Inbred C57BLABSTRACT
ABSTRACT Mutations of the GBA gene have been reported in patients with Parkinson's disease (PD) from a number of different countries, including Brazil. In order to confirm this pattern in a sample of PD patients from northern Brazil, we conducted a case-control study of the occurrence of the two most common mutations of the GBA gene (c.1226A>G; p.N370S and c.1448T>C; p.L444P) in a group of 81 PD patients and 81 control individuals, using PCR-RFLP, confirmed by the direct sequencing of the PCR products. In the patient group, three patients (3.7%) were heterozygous for the GBA c.1226A>G; p.N370S mutation, and three (3.7%) for GBA c.1448T>C; p.L444P Neither mutation was detected in the control group (p =0.0284). Patients with the c.1448T>C; p.L444P mutation showed a tendency to have an earlier disease onset, but a larger sample number is required to confirm this observation. Our results suggest an association between the GBA c.1226A>G; p.N370S and c.1448T>C; p.L444P mutations and the development of PD in the population of patients from the Northern Brazil.
RESUMO Mutações no gene GBA têm sido reportadas em pacientes com doença de Parkinson (DP) em diferentes países, incluindo o Brasil. Com o objetivo de confirmar esse padrão em uma amostra de pacientes com DP provenientes do Norte brasileiro, foi conduzindo esse estudo caso-controle investigando a frequência das duas mutações mais comuns do gene GBA (c.1226A>G; p.N370S e c.1448T>C; p.L444P) em um grupo de 81 pacientes com DP e 81 controles, usando PCR-RFLP e confirmado pelo sequenciamento direto de produtos de PCR. No grupo experimental, três pacientes (3,7%) foram heterozigotos para a mutação c.1226A>G; p.N370S e três (3,7%), para a mutação c.1448T>C; p.L444P Nenhuma das duas mutações foi detectada no grupo controle (p =0,0284). Pacientes com a mutação c.1448T>C; p.L444P demonstraram uma tendência a apresentar os sintomas mais precocemente, porém um número amostrai maior é necessário para confirmar essa observação. Nossos resultados sugerem uma associação entre essas duas mutações no gene GBA e o desenvolvimento de DP na população de pacientes do norte Brasileiro.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Parkinson Disease/genetics , Glucosylceramidase/genetics , Mutation/genetics , Polymorphism, Restriction Fragment Length , Brazil , Case-Control Studies , Polymerase Chain Reaction , Cross-Sectional Studies , Risk Factors , Age of Onset , Genetic Association StudiesABSTRACT
ABSTRACT Parkinson's disease (PD) and restless legs syndrome/Willis-Ekbom disorder (RLS/WED) are relatively common diseases in the realm of movement disorders. The fact that both may, as expected, co-occur and typically share a similar remarkable response to dopaminergic treatment raised the interest in exploration of additional shared features that throughout the years cruised fields as diverse as phenomenology, epidemiology, genetics, pathology, and clinical studies. In this review, we describe and critically examine the evidence and biases of a conceivable overlap of these two disorders, trying to shed light onto two main sources of confusion: (1) are PD and RLS/WED reciprocal risk factors? and (2) what are the main mimics of RLS/WED in PD?
RESUMO A doença de Parkinson (DP) e a síndrome das pernas inquietas/doença de Willis-Ekbom (SPI/DWE) são doenças relativamente comuns no campo dos distúrbios do movimento. O fato de que ambas podem, como esperado, ocorrer de forma simultânea e usualmente apresentarem resposta favorável ao tratamento dopaminérgico levaram ao interesse em explorar características compartilhadas adicionais. Ao longo dos últimos anos, essa busca percorreu campos diversos como a fenomenologia, epidemiologia, genética, patologia e estudos clínicos. Nesta revisão, analisamos e discutimos criticamente as evidências e os vieses de sobreposição concebíveis dessas duas doenças, tentando esclarecer duas perguntas sem resposta precisa até o momento: (1) DP e SPI/DWE representam fatores de risco recíprocos? e (2) quais são os principais mimetizadores da SPI/DWE na DP?
Subject(s)
Humans , Parkinson Disease/physiopathology , Parkinson Disease/drug therapy , Restless Legs Syndrome/physiopathology , Restless Legs Syndrome/drug therapy , Dopamine Agents/therapeutic use , Parkinson Disease/diagnosis , Parkinson Disease/genetics , Restless Legs Syndrome/diagnosis , Restless Legs Syndrome/genetics , Risk Factors , Treatment Outcome , Diagnosis, DifferentialABSTRACT
Brain-derived neurotrophic factor (BDNF) is widely expressed in the central nervous system and prolongs the survival of dopaminergic neurons in the substantia nigra. Several studies have recently investigated the association between BDNF G196A (Val66Met), a single nucleotide polymorphism influencing cognitive processes, and cognitive impairment in Parkinson's disease (PD), but with contradictory findings. Thus, this meta-analysis was performed to clarify the possible association. Relevant studies were identified by a systematic search of PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases. The strength of the association was evaluated using crude odds ratios and 95% confidence interval. Finally, six studies involving 532 cases and 802 controls were included. Our analyses suggested the G196A (Val66Met) polymorphism was significantly associated with cognitive impairment in PD, especially in Caucasian populations. In conclusion, BDNF G196A (Val66Met) is confirmed to be a risk factor for cognitive impairment in PD.
Subject(s)
Humans , Male , Female , Parkinson Disease/genetics , Brain-Derived Neurotrophic Factor/genetics , Cognitive Dysfunction/genetics , Parkinson Disease/complications , Case-Control Studies , Odds Ratio , Risk Factors , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , White People , Alzheimer Disease/complications , Cognitive Dysfunction/complications , GenotypeABSTRACT
ABSTRACT Among the candidate genes for Parkinson’s disease (PD), SNCA has replicated association in different populations. Besides other known mutations in the SNCA gene, the rs3857059 variant has also been linked to various neurodegenerative disorders. Therefore, the aim of the present study was to search for association of this variant and sporadic PD in Mexican Mestizo patients. A case-control study was performed including 241 individuals, 106 patients, and 135 healthy controls. Genotyping was performed using real-time PCR. The rs3857059 variant demonstrated an association with PD in Mexican Mestizos (OR = 2.40, CI, 1.1 to 5.1, p = 0.02) under the recessive model. In addition, a gender effect was found for the GG genotype in females (OR = 1.31, CI, 1.01 to 1.7, p = 0.037). This is the first study to confirm an association of the rs3857059 variant with PD and also to show a gender effect. Our data contribute to the elucidation of the link between rs3857059 and susceptibility to PD observed in the Mexican Mestizo population.
RESUMO Entre genes candidatos para a doença de Parkinson (PD), SNCA foi replicado em diferentes populações. Além de outras mutações conhecidas no gene SNCA, a variante rs3857059 também tem sido associada a várias doenças neurodegenerativas. Portanto, o objetivo do presente estudo foi o de procurar variante de associação e PD esporádica em pacientes mestiços mexicanos. Um estudo de caso-controle foi executado, incluindo 241 indivíduos, 106 pacientes e 135 controles saudáveis. A genotipagem foi realizada utilizando PCR em tempo real. A variante rs3857059 se mostrou associada a PD em mexicano-mestiços (OR = 2,40, IC 1,1-5,1, p = 0,02) sob o modelo recessivo. Além disso, um efeito de gênero foi encontrado para o genótipo GG no sexo feminino (OR = 1,31, CI, 1,01-1,7, p = 0,037). Este é o primeiro estudo que confirma associação da variante rs3857059 para a PD e também um efeito de gênero. Nossos dados contribuem para elucidar suscetibilidade à PD observada na população mexicana-mestiça.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Parkinson Disease/genetics , alpha-Synuclein/genetics , Mutation/genetics , Parkinson Disease/ethnology , Case-Control Studies , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Real-Time Polymerase Chain Reaction , Gene Frequency , Genotype , Mexico/ethnologyABSTRACT
Genetic susceptibility, is considered to be involved in neurodegenerative diseases such as Alzheimer's disease [AD] and Parkinson's disease [PD]. Despite the fact that many susceptibility genes for AD and PD have been considered, the most probable genetic risk factor which has been taken into consideration is Apolipoprotein E genotype located on chromosome 19q, APOE is the gene widely considered to be a susceptibility gene for neurodegenerative diseases. This study is to investigate the association of APOE polymorphism with AD and PD. In this case control study we examined association of an APOE gene polymorphism [rs121918398] with AD and PD in Iranian population. The study included 100 AD patients, 100 PD patients and 150 healthy volunteers. An informed consent was obtained from all participants. Genomic DNA was extracted from peripheral blood leukocyte. Genotypes were determined by PCR and restriction fragment length polymorphism [RFLP] by Hha1 restriction enzyme. Sequencing of PCR products was carried out by Fazabiotech Company according to Sanger method using ABI 3730XL Capillary Sequencer. Statistical analysis was performed using the MedCalc program. The prevalence of genotype frequencies of the APOE A/A, A/G, G/G were 16%, 34% and 50% in AD subjects, 14%, 32%, 54% in PD patients and in healthy volunteers were 15%, 39% and 96% respectively. Statistical analysis showed no significant difference between genotype frequencies of AD and those of control subjects [P < 0.05]. Moreover, according to statistical analysis, the genotype frequencies of APOE in PD subjects and control group did not significantly differ. This is the very first time that the association of this polymorphism [rs121918398] with AD is being reported nevertheless, there is no evidence that APOE variant is associated with PD. Accordingly, genotype alteration of A8390>G can't be related to AD. So, this polymorphism plays no pathogenic role in the PD and AD patients in Iranian population
Subject(s)
Aged , Aged, 80 and over , Female , Humans , Male , Alzheimer Disease/genetics , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Case-Control Studies , Genetic Association StudiesABSTRACT
BACKGROUND:Parkinson's disease (PD); with a prevalence of up to 4% in Western countries; appears to be less common in Africa; possibly in part because of genetic factors. African studies investigating the genetic causation of PD are limited. OBJECTIVE:To describe the clinical and genetic findings in a group of black South African patients with PD.METHODS:All black African patients with PD from a tertiary hospital neurology clinic were examined. Symptoms were scored according to the Unified Parkinson's Disease Rating Scale (UPDRS); and patients were classified according to motor features. Genomic DNA was extracted and multiplex ligation-dependent probe amplification was used for detection of copy number variation (CNV) mutations in the known PD-causing genes.RESULTS:Sixteen patients were identified (ages 56 - 82 years). Three had a family history of PD. Classification into motor subtypes showed 44% mixed; 31% akinetic-rigid; and 25% tremor-dominant subtypes. UPDRS scores ranged from 7 to 88; with dementia in 20%. No patient had G2019S LRRK2 and A30P SNCA mutations; and all except one had no CNV mutations in the known PD-causing genes. A female patient (age of onset 50 years; no family history) had a parkin gene heterozygous deletion of exon 4. She had hyperreflexia; bilateral Hoffmann's reflexes; normal plantar responses and no dystonia.CONCLUSION:This group of black African patients showed similar characteristics to patients in Western studies; possibly with a higher proportion having tremor-dominant disease. Genetic analysis showed one parkin gene mutation. The limited knowledge on PD-causing genes and mutations in black populations warrants further studies involving next-generation sequencing approaches
Subject(s)
Cohort Effect , Parkinson Disease/diagnosis , Parkinson Disease/epidemiology , Parkinson Disease/geneticsABSTRACT
Introduction: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson's disease, but the prevalence of these mutations varies among populations. Objective: To analyzed the frequency of the LRRK2 p.G2019S mutation (c.6055G>A transition) in a sample of Colombian patients. Methods: In the present study we have analyzed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls. Results: Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson's signs, and one completely asymptomatic control (1/162, 0.6%). Conclusion: The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations.
Introducción: Las mutaciones en el LRRK2 (del inglés gen leucinerich repeat kinase 2) o Dardarina se consideran una causa común de enfermedad de Parkinson autosómica dominante. Sin embargo, la prevalencia de estas mutaciones varia en diferentes poblaciones. Objetivo: Snalizar la frecuencia de la mutación p.G2019S (transición c.6055 G>A) del gen LRRK2en una muestra de pacientes colombianos. Métodos: En el presente estudio analizamos la frecuencia de la mutación en 154 pacientes con enfermedad de Parkinson familiar o esporádica, y 162 controles normales. Resultados: Se determinó la presencia de la mutación en 2 casos de Parkinson (2/154, 1.3%) los cuales presentan los signos clásicos de la enfermedad y en un control completamente asintomático (1/162, 0.6%). Conclusión: La mutación p.G2019S no es un factor causal importante de la Enfermedad de Parkinson en la población Colombiana, y muestra frecuencias similares a las reportadas en otras poblaciones latinoamericanas.
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Gene Frequency , Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Age of Onset , Case-Control Studies , Colombia , Genetic Predisposition to Disease , Mutation , Parkinson Disease/physiopathologyABSTRACT
Introduction The pathogenesis of Parkinson’s disease (PD) involves both genetic susceptibility and environmental factors, with focus on the mutation in the alpha-synuclein gene (SNCA).Objective To analyse the polymorphism SNCA-A53T in patients with familial PD (FPD) and sporadic PD (SPD).Method A total of 294 individuals were studied, regardless of sex and with mixed ethnicity. The study group with 154 patients with PD, and the control group included 140 individuals without PD. The genotyping of SNCA-A53T was performed by PCR/RFLP. Significance level was p < 0.05.Results Among all patients, 37 (24%) had FPD and 117 (75.9%) had SPD. The absence of SNCA-A53T mutation was observed in all individuals.Conclusion SPD is notably observed in patients. However, the SNCA-A53T mutation was absent in all individuals, which does not differ controls from patients. This fact should be confirmed in a Brazilian study case with a more numerous and older population.
Introdução A patogênese da doença de Parkinson (DP) envolve fatores ambientais e suscetibilidade genética, destacando-se a mutação de alfa-sinucleína (SNCA.)Objetivos Analisar a variante genética SNCA-A53T em pacientes com DP familiar (DPF) e DP esporádica (DPE).Método Foram estudados 294 indivíduos, independente de sexo, com etnia miscigenada, sendo 154 com DP e 140 sem a doença (grupo controle). A genotipagem de SNCA-A53T foi realizada por PCR/RFLP. Nível de significância para p < 0,05.Resultados Entre os pacientes, 37(24%) tinham DPF e 117 (75,9%) DPE. A ausência da mutação SNCA-A53T em todos os indivíduos.Conclusão DPE é destacada entre os pacientes, no entanto a mutação SNCA-A53T ausente em todos os indivíduos, não diferenciando os grupo controle e pacientes, o que deve ser confirmado em população brasileira, considerando uma ampla casuística, além da ancestralidade.
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Mutation , Parkinson Disease/genetics , Polymorphism, Restriction Fragment Length/genetics , alpha-Synuclein/genetics , Brazil , Case-Control Studies , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Polymerase Chain Reaction , Sex FactorsABSTRACT
Introduction Mucoceles are benign expansive cystic formations, composed of a mucus-secreting epithelium (respiratory or pseudostratified epithelium). Nasolacrimal mucocele occurs in a small proportion of children with nasolacrimal duct obstruction and is characterized by a cystic mass in the medial canthus with dilation of the nasolacrimal duct; although dacryocystoceles are rare in adults, they have been reported in patients with trachoma. Objective Discuss clinical aspects, diagnosis, and therapeutic management of mucocele of nasolacrimal duct based on literature review. Resumed Report The authors report a case of bilateral congenital nasolacrimal duct cysts in a 30-year-old man, identified as a tumor in the topography of both lacrimal sacs since birth without associated symptoms. The patient underwent successive surgical treatments, leading to recurrence of the tumor at the right side and recurrent local infections. Conclusion Endoscopic dacryocystorhinostomy has been increasingly used with good results and success rates similar to the external access. .
Subject(s)
Animals , Humans , Genetic Predisposition to Disease/genetics , Mutation/genetics , Nervous System Diseases/genetics , Sodium-Potassium-Exchanging ATPase/genetics , Databases, Bibliographic/statistics & numerical data , Hemiplegia/genetics , Models, Molecular , Nervous System Diseases/diagnosis , Parkinson Disease/genetics , Sodium-Potassium-Exchanging ATPase/metabolismSubject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Ambroxol/pharmacology , Fibroblasts/drug effects , Glucosylceramidase/genetics , Mutation/genetics , Parkinson Disease/pathology , Cells, Cultured , Fibroblasts/metabolism , Gene Expression Profiling , Gaucher Disease/complications , Gaucher Disease/genetics , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Glucosylceramidase/metabolism , Glycoside Hydrolases/pharmacology , Neuroblastoma/pathology , Oxidative Stress/drug effects , Parkinson Disease/complications , Parkinson Disease/geneticsABSTRACT
Parkinson's disease (PD) is an age-related progressive neurodegenerative disease associated with selective loss of dopaminergic neurons. The characteristic hallmark of the disease is intracytoplasmic proteinacious inclusion bodies called Lewy bodies, primarily consisting of a presynaptic protein alpha-synuclein. Oxidative stress-mediated damage to macromolecules have been shown to occur frequently in PD. Oxidative damage to DNA in the form of oxidized guanine (8-oxodG) accumulates in both the mitochondrial and nuclear DNA of dopaminergic neurons of the substantia nigra in PD. 8-oxodG-mediated transcriptional mutagenesis has been shown to have the potential to alter phenotype of cells through production of mutant pool of proteins. This review comprehensively summarizes the role of oxidative stress-mediated damage incurred during neurodegeneration, and highlights the scope of transcriptional mutagenesis event in leading to alpha-synuclein aggregation as seen in PD.
Subject(s)
Animals , Humans , Amino Acid Sequence , Deoxyguanosine/analogs & derivatives , Molecular Sequence Data , Mutagenesis , Oxidative Stress , Parkinson Disease/genetics , Protein Aggregation, Pathological/genetics , Substantia Nigra/metabolism , Transcription, Genetic , alpha-Synuclein/chemistryABSTRACT
Mutations in the LRRK2 gene, predominantly G2019S, have been reported in individuals with autosomal dominant inheritance and sporadic Parkinson’s disease (PD). The G2019S mutation has an age-dependent penetrance and evidence shows common ancestry. The clinical manifestations are indistinguishable from idiopathic PD. Its prevalence varies according to the population studied ranging from less than 0.1% in Asians to 41% in North African Arabs. This study aimed to identify G2019S mutation in Brazilian idiopathic PD patients. Method: We sampled 100 PD patients and 100 age- and gender-matched controls. Genetical analysis was accomplished by polymerase chain reaction (PCR). Results: No G2019S mutations were found in both patients with sporadic PD and controls. Conclusions: Our results may be explained by the relatively small sample size. .
Mutação no gene LRRK2, predominantemente G2019S, foi descrita em indivíduos com doença de Parkinson (DP) esporádica ou herança autossômica dominante. A penetrância da mutação varia com a idade e há evidências de ancestral comum. As manifestações clínicas são indistinguíveis da DP idiopática. Sua prevalência depende da população estudada e varia de 0,1% em asiáticos a 41% em árabes do norte africano. O objetivo desse estudo foi identificar a mutação G2019S em brasileiros com DP esporádica. Método: Foram testados 100 pacientes com DP e 100 controles pareados por idade e sexo. A análise genética foi realizada pela reação em cadeia por polimerização (PCR). Resultados: Não foi encontrada a mutação G2019S nem nos pacientes com DP nem nos controles. Conclusão: É possível que nossos resultados sejam devidos ao pequeno número de pacientes incluídos. .
Subject(s)
Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Mutation Rate , Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Age Factors , Age of Onset , Brazil , Case-Control Studies , Polymerase Chain Reaction , Parkinson Disease/ethnologyABSTRACT
In view of documented evidence demonstrating the association of dopaminergic metabolism and neurotransmission with Parkinson’s disease (PD), a case-control study was conducted to investigate the impact of particular polymorphisms in the catechol O-methyl transferase (COMT) H108L, monoamine oxidase B (MAOB) int 13 A>G, dopamine transporter 1 (DAT1) A1215G, dopamine receptor D2 (DRD2) Taq1A, DRD2 Taq1B and DRD2 Taq1D genes on the susceptibility to PD. PCR-RFLP method was used for the genetic analysis. The COMT H108L polymorphism increased PD risk by 1.4-fold (95%CI: 1.02-1.98), whereas reduced risk was observed with MAOB int 13 A>G polymorphism (OR: 0.77, 95%CI: 0.51-0.99). Multifactor dimensionality reduction analysis showed gene-gene interactions between these two loci that resulted in loss of the protective role of MAOB G-allele in the presence of COMT L-allele. DAT1A1215G polymorphism in the exon 9 was not associated with PD. Individually, DRD2 polymorphisms showed null association. However, all-variant haplotype of DRD2 locus i.e. T-G-T haplotype showed 29.8-fold risk for PD compared to all-wild haplotype i.e., C-A-C haplotype (95%CI: 6.85-130.4). To conclude, genetic variants of COMT, MAOB and DRD2 loci modulate susceptibility to PD in South Indian subjects.
Subject(s)
Catechol O-Methyltransferase/genetics , Female , Genetic Predisposition to Disease/genetics , Haplotypes , Humans , India , Male , Middle Aged , Monoamine Oxidase/genetics , Parkinson Disease/enzymology , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Receptors, Dopamine D2/geneticsABSTRACT
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.
Fatores genéticos e ambientais influenciam a patogênese da doença de Parkinson (DP). Variantes genéticas das enzimas glutationa S-transferases (GST) parecem estar envolvidas com a doença. Os objetivos deste estudo foram avaliar a influência de variantes genéticas de GST (GSTT1/GSTM1) e sua associação com exposição a toxinas ambientais em pacientes com DP. Foram estudados 254 pacientes com DP e 169 controles. As variantes para GSTM1/GSTT1 foram analisadas por reação em cadeia da polimerase. Para análise estatística foram aplicados os testes de Fisher e do χ2 (p<0,05). Tanto a presença quanto a nulidade para GSTT1 e GSTM1 foram semelhantes em pacientes e controles. A nulidade para GSTT1 e GSTM1 (0/0) e contato com agrotóxicos prevaleceu nos pacientes (18%) em relação aos controles (13%, p=0,014). Este estudo sugere associação entre DP e contato prévio com agrotóxicos, cujo efeito parece potencializado em combinação com nulidade para GSTT1/GSTM1.
Subject(s)
Aged , Female , Humans , Male , Glutathione Transferase/genetics , Parkinson Disease/enzymology , Pesticides/toxicity , Case-Control Studies , Gene-Environment Interaction , Genetic Predisposition to Disease , Genotype , Polymerase Chain Reaction , Polymorphism, Genetic , Parkinson Disease/genetics , Risk FactorsABSTRACT
To investigate the association of five SNPs (rs823083, rs708723, rs4951261, rs823076 and rs16856110) at the PARK16 locus with Parkinson's disease (PD), and to potentiate its forensic application. The genomic DNAs of 215 PD patients and 212 matched controls from the northern Han Chinese population were amplified in two independent PCR systems and subsequently genotyped by digestion with the three endonucleases (Hinf I, Nco I and Msp I ). The genetic parameters and association studies were carried out with SPSS 13.0, Haploview version 4.2 and PLINK 1.07 softwares. We detected accurately all genotypes in the five SNPs with multiplex PCR-RFLP and mismatched multiplex PCR-RFLP techniques. The genotypes of four SNPs, except for rs823083, were in Hardy-Weinberg equilibrium. The four SNPs, rs16856110, rs4951261, rs708723 and rs823076, which were in linkage equilibrium, should not be associated with PD (P-values ranging from 0.077 to 0.544). The SNPs investigated at the PARK16 locus were not found to be involved in PD-associated blocks in the northern Han Chinese population. The allele distributions of rs708723, rs4951261, rs823076 and rs16856110 in the northern Han Chinese population can be highly polymorphic, which can be applied to genetic analysis and forensic practices.
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Asian People/genetics , Case-Control Studies , Forensic Genetics , Gene Frequency , Genetic Association Studies , Genetic Loci , Genetic Predisposition to Disease , Genotype , Parkinson Disease/genetics , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Polymorphism, Single NucleotideABSTRACT
A doença de Parkinson (DP) é uma das desordens neurodegenerativas mais comuns associada ao envelhecimento, alcançando 2% aos 70 anos. É uma doença caracterizada pela degeneração progressiva de neurônios dopaminérgicos nigrais nos gânglios basais e pela presença de inclusões protéicas citoplasmáticas denominadas corpúsculos e neuritos de Lewy nos neurônios sobreviventes. A etiologia da DP é pouco conhecida, sendo considerada, na maioria dos casos, idiopática. Conhecimentos alcançados nos últimos 15 anos sobre a base genética da DP demonstram, claramente, que os fatores genéticos desempenham um importante papel na etiologia desta desordem. Neste trabalho, rastreamos mutações nos genes que codificam proteínas participantes de vias metabólicas mitocondriais (Parkin, PINK1 e DJ-1) em 136 pacientes brasileiros com manifestação precoce da DP, através do sequenciamento automático e da técnica de MLPA. Avaliamos a presença de variantes de sequência por meio do sequenciamento dos exons 1 a 12 do gene Parkin e dos exons 1 a 8 do gene PINK1. Em Parkin foram identificadas três mutações patogênicas ou potencialmente patogênicas, ambas em heterozigose: p.T240M, p.437L e p.S145N. Em PINK1 não encontramos variantes de ponto patogênicas. Através da técnica de MLPA investigamos alterações de dosagem nos genes Parkin, PINK1 e DJ-1. Identificamos cinco alterações no gene Parkin em quatro pacientes: uma duplicação heterozigota do exon 4 no paciente PAR2256, uma deleção heterozigota do exon 4 no probando PAR2099, uma deleção homozigota do exon 4 na paciente PAR3380 e um probando heterozigoto composto (PAR2396) com duas alterações, uma duplicação do exon 3 e uma deleção dos exons 5 e 6. No gene PINK1 identificamos uma deleção heterozigota do exon 1, que nunca foi descrita na literatura, em um paciente (PAR2083). Não encontramos alteração quantitativa no gene DJ-1. Neste estudo obtivemos uma frequência total de mutações patogênicas (pontuais e de dosagem) nos genes estudados ...
Parkinson's disease (PD) is one of the most common neurodegenerative disorders associated with aging, reaching 2% at age 70. It is a disease characterized by progressive degeneration of nigra dopaminergic neurons in the basal ganglia and the presence of cytoplasmic protein inclusions known as Lewy bodies and neurites in surviving neurons. The etiology of PD is poorly understood, being considered, in most cases, idiopathic. Knowledge achieved in the last 15 years about the genetic basis of PD clearly shows that genetic factors play an important role in the etiology of this disorder. In this study, we screened mutations in genes that encode proteins participating in mitochondrial metabolic pathways (Parkin, PINK1 and DJ-1) in 136 Brazilian patients with early onset PD, through automatic sequencing and MLPA technique. We evaluated the presence of sequence variants by means of sequencing of exons 1 to 12 of Parkin gene and exons 1 to 8 of PINK1 gene. In Parkin gene were identified three pathogenic or potentially pathogenic mutations, both in heterozygous state: p.T240M, p.437L e p.S145N. In PINK1 gene we did not find pathogenic point mutations. Through the MLPA technique we investigated dosage changes in Parkin, PINK1 and DJ-1 genes. We identified five exon rearrangements in Parkin gene in four patients: a heterozygous duplication of exon 4 in patient PAR2256, a heterozygous deletion of exon 4 in proband PAR2099, a homozygous deletion of exon 4 in patient PAR3380 and a compound heterozygote (PAR2396) with two changes, a duplication of exon 3 and a deletion of exons 5 and 6. In PINK1 gene we identified a heterozygous deletion of exon 1, which has never been described in literature, in one patient (PAR2083). We found no quantitative change in DJ-1 gene. In this study, we obtained an overall frequency of pathogenic mutations (sequence and dosage) in the genes studied of 7.3%, being 6.6% in Parkin gene and 0.7% in PINK1 gene