31 research outputs found

    Aspectos gen√©ticos, ambientais e suas intera√ß√Ķes na suscetibilidade e farmacogen√©tica da doen√ßa de Parkinson

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    A doen√ßa de Parkinson (DP) √© a segunda doen√ßa neurodegenerativa mais frequente na esp√©cie humana. A etiologia da DP √© multifatorial, com muitos fatores ambientais e gen√©ticos atuando em conjunto para sua determina√ß√£o. Ao n√≠vel patol√≥gico ela caracteriza-se pela destrui√ß√£o seletiva de neur√īnios dopamin√©rgicos da substantia nigra pars compacta e pelo ac√ļmulo de corpos de Lewy no c√©rebro. Em aproximadamente 90% dos casos da DP, a suscetibilidade parece ser determinada por variantes comuns no genoma que podem interagir com o ambiente. Dentre os fatores ambientais que modulam o risco para a DP est√£o: uso de pesticidas, exposi√ß√£o ocupacional a t√≥xicos, consumo de caf√© e cigarro. A variabilidade na resposta √† principal medica√ß√£o da DP, a levodopa, parece tamb√©m estar relacionada √† gen√©tica do indiv√≠duo. Dessa forma, o presente trabalho teve como objetivo a melhor compreens√£o dos fatores gen√©ticos e suas intera√ß√Ķes com o ambiente envolvidos na suscetibilidade √† DP e no tratamento com levodopa. Pacientes com DP e seus controles foram recrutados no ambulat√≥rio de dist√ļrbios do movimento e no ambulat√≥rio de medicina interna do Hospital de Cl√≠nicas de Porto Alegre e da Universidade Federal de Ci√™ncias da Sa√ļde de Porto Alegre, respectivamente. Os resultados obtidos foram organizados em cinco artigos. No primeiro estudo, foram considerados oito polimorfismos previamente associados √† DP. Na nossa popula√ß√£o, os indiv√≠duos que possu√≠am sete ou mais alelos de risco desses polimorfismos apresentaram um odds ratio de 2,54 quando comparados a quem possu√≠a seis alelos ou menos (95% IC 1,66-3,89; P = 1,80E‚ąí05). Esse ponto de corte foi escolhido porque o n√ļmero m√©dio de alelos de risco na amostra foi 7. No segundo artigo, portadores do gen√≥tipo TT do polimorfismo rs1021463 e dos gen√≥tipos TT ou GT do polimorfismo rs30196 do gene SV2C apresentaram um maior risco a DP quando expostos ocupacionalmente a t√≥xicos, quando comparado a n√£o-expostos (respectivamente, OR 2,53; 95% IC 1,33-4,69; Pintera√ß√£o = 0,008 e OR 2,30; 95% IC 1,21-4,36; Pintera√ß√£o = 0,033). O terceiro artigo mostra uma associa√ß√£o em que fumantes com o hapl√≥tipo T- n√£o G -T do transportador ABCB1 apresentaram menor risco a DP quando comparados a portadores do 9 hapl√≥tipo C-G-C (OR 0,34, 95% IC 0,15-0,72; Pintera√ß√£o = 0,012). No quarto trabalho, foi constatada uma intera√ß√£o entre o gene NOS1 e a cafe√≠na modulando o risco da DP (OR 0,24; 95% IC 0,10-0,54; Pintera√ß√£o = 0,0002). O √ļltimo artigo trata da farmacogen√©tica da levodopa, em que foi proposto um modelo com vari√°veis gen√©ticas, biol√≥gicas e farmacol√≥gicas que explicou 23% da variabilidade na dose (F = 11,54; P < 0,000001). Observou-se uma redu√ß√£o da m√©dia de dose em aproximadamente 76 mg/dia por cada alelo C nos gen√≥tipos do polimorfismo rs30196 do gene SV2C. Estes trabalhos enriqueceram o conhecimento da variabilidade da DP tanto em aspectos de suscetibilidade quanto farmacogen√©tica. Os dados obtidos ser√£o importantes na continua√ß√£o das pesquisas para identificar biomarcadores para preven√ß√£o e tratamento da DP.Parkinson‚Äôs disease (PD) is the second most common neurodegenerative disease in humans. PD etiology is multifactorial, due to several environmental and genetic factors. Pathologically, it is characterized by a selective destruction of dopaminergic neurons in substantia nigra pars compacta and by the accumulation of Lewy bodies in brain. In approximately 90% of PD cases, susceptibility seems to be driven by common variants in the genome that might interact with the environment. Among environmental factors that modulate PD risk, pesticides, occupational exposure to toxics, smoking and coffee consumption were identified. The variability in patients‚Äô response to the main medication of PD, levodopa, seems also to be related to genetics. Therefore, the present work had the objective to understand the genetic factors and their interaction with the environment involved in PD susceptibility and in the treatment with levodopa. Patients and controls were recruited at the movement disorders ambulatory and at the internal medicine ambulatory at the Hospital de Cl√≠nicas de Porto Alegre and at Universidade Federal de Ci√™ncias da Sa√ļde de Porto Alegre respectively. The main results obtained were organized in five manuscripts. In the first, eight polymorphisms previously associated with PD were considered. In our population, individuals with 7 or more risk alleles presented an odds ratio of 2.54 for PD when compared to those with 6 or less alleles (95% CI 1.66-3.89; P = 1.80E‚ąí05). This cut off was chosen because the average number of risk alleles in the sample was 7. In the second manuscript, SV2C rs10214163 TT genotype carriers and SV2C rs30196 TT/GT genotypes carriers showed a higher PD risk in subjects exposed to environmental toxics compared to those not exposed (respectively, OR 2.53; 95% CI 1.33-4.69; Pinteraction = 0.008 and OR 2.30; 95% CI 1.21-4.36; Pinteraction = 0.033). The third manuscript shows the association between ABCB1 T-non G-T haplotype and smoking (OR 0.34, 95% CI 0.15-0.72; Pinteraction = 0.012). In the fourth manuscript, an interaction between NOS1 gene and caffeine, modulating PD risk, was observed (OR 0.24; 95% CI 0.10-0.54; Pinteraction = 0.0002). The last manuscript reports a 11 model with genetic, biological and pharmacological variants in response to levodopa. This model explained 23% of dose variability (F = 11.54; P < 0.000001). The presence of each rs30196 C allele reduced the average dose in approximately 76 mg/day. All these work enriched the knowledge of the variability of PD in both susceptibility and pharmacogenetic areas. The data obtained will be important to identify biomarkers for disease prediction and treatment

    Influência de variantes do gene do fator neurotrófico derivado do cérebro e da apolipoproteína e no déficit cognitivo da doença de Parkinson

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    A doen√ßa de Parkinson (DP) possui preval√™ncia de 3,3% na popula√ß√£o brasileira. Essa doen√ßa √© caracterizada por sintomas motores caracter√≠sticos. Os pacientes com DP apresentam tamb√©m sintomas n√£o motores como o d√©ficit cognitivo. Esse sintoma prejudica a qualidade de vida dos pacientes e pode progredir ao longo do tempo. O d√©ficit cognitivo n√£o possui uma neuropatologia bem compreendida. V√°rios estudos sugerem que a etiologia desse sintoma seja devida pelo menos em parte ao perfil gen√©tico do paciente. No presente trabalho, foram analisados dois genes envolvidos com a neuroplasticidade sin√°ptica, o BDNF e a APOE e sua poss√≠vel associa√ß√£o com a ocorr√™ncia de d√©ficit cognitivo na Doen√ßa de Parkinson. O BDNF √© relacionado √† sobreviv√™ncia, diferencia√ß√£o e manuten√ß√£o dos neur√īnios, e tamb√©m com a forma√ß√£o de mem√≥ria. Um polimorfismo na regi√£o codificante (Val66Met) nesse gene est√° relacionado a uma menor secre√ß√£o de prote√≠na. A APOE interage com neur√īnios, promovendo sinaptog√™nese, crescimento axonal, reparo de nervos e na preven√ß√£o de morte neuronal. Essa lipoprote√≠na possui tr√™s isoformas codificadas pelos alelos őĶ2, őĶ3 e őĶ4. O alelo őĶ4 foi previamente associado a dem√™ncia na DP em alguns estudos. Um total de 163 pacientes com DP idiop√°tica foram diagnosticados e recrutados no ambulat√≥rio de Dist√ļrbios do Movimento no Hospital de Cl√≠nicas de Porto Alegre. Todos os indiv√≠duos foram genotipados para os polimorfismos dos genes BDNF e APOE por t√©cnicas baseadas em PCR. A escala do Mini Mental Test Examination (MMSE) foi utilizada para definir a ocorr√™ncia de d√©ficit cognitivo Pacientes portadores do alelo 66Met do gene do BDNF apresentaram maior preval√™ncia de d√©ficit cognitivo (p=0,006; PR=1,52; IC=95% [1,12-2,05]). Em rela√ß√£o a APOE, n√£o foi encontrada associa√ß√£o do alelo őĶ4 com d√©ficit cognitivo na DP (p=0,393; PR=1,15; IC=95% [0,84-1,58]). Esses resultados corroboram trabalhos anteriores que descrevem associa√ß√Ķes gen√©ticas com d√©ficit cognitivo na DP e sugerem que o BDNF possa ter um importante papel na patog√™nese do d√©ficit cognitivo na doen√ßa de Parkinson.Parkinson's disease (PD) has a prevalence of 3.3% in the Brazilian population. This disease is characterized by motor symptoms. However patients with this disease also present non-motor symptoms as cognitive impairment. This symptom greatly affects functioning and patient`s quality of life. The Cognitive impairment neuropathology is still not elucidated. Several studies suggested that its etiology is due, at least in part, to patient`s genetic profile. In the present study, two genes related to neuroplasticity were investigated, BDNF and APOE. BDNF is related to survival, differentiation and neuron maintenance, as well as memory formation. A coding polymorphism in this gene (Val66Met) is related to impaired secretion of the BDNF protein. APOE interacts with neurons, promoting synaptogenesis stimulation, axonal growth, nerve repair and prevent neuronal death. This protein has three isoforms coded by the őĶ2, őĶ3 and őĶ4 alleles. Allele őĶ4 was previously associated with dementia in Parkinson's disease in studies. A total of 163 patients were diagnosed and recruited at the Movement Disorders clinics at "Hospital de Cl√≠nicas de Porto Alegre. All individuals were genotyped for polymorphisms in BDNF and APOE by PCR based methods. Cognitive impairment diagnosis was based on the Mini Mental Test Examination (MMSE). Carriers of BDNF 66Met allele presented a higher prevalence of cognitive impairment (p=0.006, PR=1.52, 95% CI [1.12-2.05]). However, no association was observed for őĶ4 carriers with cognitive impairment (p=0.393, PR=1.15, 95% CI [0.84-1.58]). These results extend previously described genetic associations with cognitive impairment in PD and suggest that BDNF might play a role in the pathogenesis of cognitive impairment in Parkinson's disease

    A case-control study of the effects of Chimarr√£o ( Ilex paraguariensis) and coffee on Parkinson's disease

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    Introduction: Coffee has been inversely associated with Parkinson's disease (PD) in many studies, and caffeine is the leading candidate to mediate this effect. Mate (Ilex paraguariensis, IP), a caffeinated beverage rich in antioxidants consumed in South America, was also inversely associated with PD in one study from Argentina. Other varieties of IP infusion, such as chimarr√£o, were never studied in PD. Chimarr√£o is a common caffeinated beverage consumed in Brazil made with the leaves and stems of IP. Methods: A case‚Äďcontrol study was conducted to evaluate the relationship between chimarr√£o ingestion and PD in southern Brazil. All subjects answered a questionnaire about the frequency of chimarr√£o and coffee intake. A multiple regression analysis adjusted for age and sex was performed to assess the association between PD and chimarr√£o consumption. Results: We included 200 PD patients and 200 healthy controls. High consumption of chimarr√£o was inversely associated with PD (OR = 0.44, 95% CI = 0.24‚Äď0.81, P = 0.008). High consumption of coffee was also inversely associated with PD, as expected. Chimarr√£o remained associated when adjusted for coffee consumption, smoking history, and age (OR 0.46, 95% CI = 0.25‚Äď0.86, P = 0.014). These two exposures showed an additive effect. Conclusion: Chimarr√£o consumption was inversely associated with PD, even after adjusting for coffee intake, suggesting a possible protective role. IP's effect can be mediated by caffeine and through its antioxidant components. Chimarr√£o has a lower concentration of caffeine compared with coffee and has numerous substances with antioxidative effects that may be important to PD protection. Further studies are needed to test this hypothesis

    A repeat protein links Rubisco to form the eukaryotic carbon-concentrating organelle.

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    Biological carbon fixation is a key step in the global carbon cycle that regulates the atmosphere's composition while producing the food we eat and the fuels we burn. Approximately one-third of global carbon fixation occurs in an overlooked algal organelle called the pyrenoid. The pyrenoid contains the CO2-fixing enzyme Rubisco and enhances carbon fixation by supplying Rubisco with a high concentration of CO2 Since the discovery of the pyrenoid more that 130 y ago, the molecular structure and biogenesis of this ecologically fundamental organelle have remained enigmatic. Here we use the model green alga Chlamydomonas reinhardtii to discover that a low-complexity repeat protein, Essential Pyrenoid Component 1 (EPYC1), links Rubisco to form the pyrenoid. We find that EPYC1 is of comparable abundance to Rubisco and colocalizes with Rubisco throughout the pyrenoid. We show that EPYC1 is essential for normal pyrenoid size, number, morphology, Rubisco content, and efficient carbon fixation at low CO2 We explain the central role of EPYC1 in pyrenoid biogenesis by the finding that EPYC1 binds Rubisco to form the pyrenoid matrix. We propose two models in which EPYC1's four repeats could produce the observed lattice arrangement of Rubisco in the Chlamydomonas pyrenoid. Our results suggest a surprisingly simple molecular mechanism for how Rubisco can be packaged to form the pyrenoid matrix, potentially explaining how Rubisco packaging into a pyrenoid could have evolved across a broad range of photosynthetic eukaryotes through convergent evolution. In addition, our findings represent a key step toward engineering a pyrenoid into crops to enhance their carbon fixation efficiency

    The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis.

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    The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 √ó 10-4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS

    Optimization of insect cell based protein production processes - online monitoring, expression systems, scale-up

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    Due to the increasing use of insect cell based expression systems in research and industrial recombinant protein production, the development of efficient and reproducible production processes remains a challenging task. In this context, the application of online monitoring techniques is intended to ensure high and reproducible product qualities already during the early phases of process development. In the following chapter, the most common transient and stable insect cell based expression systems are briefly introduced. Novel applications of insect cell based expression systems for the production of insect derived antimicrobial peptides/proteins (AMPs) are discussed using the example of G. mellonella derived gloverin. Suitable in situ sensor techniques for insect cell culture monitoring in disposable and common bioreactor systems are outlined with respect to optical and capacitive sensor concepts. Since scale-up of production processes is one of the most critical steps in process development, a conclusive overview is given about scale up aspects for industrial insect cell culture processes

    Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

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    Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain

    Influência do polimorfismo Val66Met do gene do fator neurotrófico derivado do cérebro (BDNF) no tratamento da doença de Parkinson

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    A doen√ßa de Parkinson (DP), a segunda doen√ßa neurodegenerativa mais freq√ľente e caracteriza-se pela degenera√ß√£o de neur√īnios dopamin√©rgicos da substantia nigra pars compacta do estriado, que est√° relacionada com os sintomas da doen√ßa. A Levodopa √© a medica√ß√£o mais eficaz para o controle dos sintomas motores da doen√ßa de Parkinson. Entretanto, seu uso continuado, relacionado √† plasticidade neuronal, pode provocar o surgimento de fen√īmenos indesejados, como a flutua√ß√£o motora, a discinesia e a alucina√ß√£o. O decl√≠nio cognitivo associado √† DP √© outro fator muito freq√ľente e tamb√©m dificulta o manejo e prejudica a qualidade de vida dos pacientes. O fator neurotr√≥fico derivado do c√©rebro (BDNF) √© uma prote√≠na altamente expressa no sistema nervoso central. O BDNF promove sobreviv√™ncia, diferencia√ß√£o, manuten√ß√£o dos neur√īnios e plasticidade sin√°ptica estando inclu√≠dos os neur√īnios dopamin√©rgicos da substantia nigra. Um polimorfismo (G196A) na regi√£o codificadora deste gene determina a substitui√ß√£o de uma valina por uma metionina no c√≥don 66 da prote√≠na. O objetivo do presente estudo foi determinar a influ√™ncia do polimorfismo Val66Met do gene BDNF na dose equivalente de levodopa utilizada por pacientes com doen√ßa de Parkinson, no desenvolvimento de decl√≠nio cognitivo e na ocorr√™ncia de discinesias, alucina√ß√Ķes e flutua√ß√Ķes motoras induzidas por esse medicamento. Cento e setenta e dois pacientes em atendimento no Ambulat√≥rio de Dist√ļrbios do Movimento no Hospital de Cl√≠nicas de Porto Alegre com diagn√≥stico de doen√ßa de Parkinson idiop√°tica foram inclu√≠dos no estudo. As amostras de DNA foram extra√≠das pelo m√©todo de salting out, a partir de sangue perif√©rico. O polimorfismo foi amplificado pela t√©cnica de PCR. Os produtos de amplifica√ß√£o foram clivados com Eco72I e visualizados por eletroforese em gel de agarose a 3,5% corado com brometo de et√≠dio. As freq√ľ√™ncias genot√≠picas foram AA (4,1%), AG (27,3%) e GG (68,6%). Os tr√™s gen√≥tipos n√£o apresentaram efeito significativo quanto √† dose equivalente, a presen√ßa de discinesias, alucina√ß√Ķes e flutua√ß√Ķes motoras. Por√©m os gen√≥tipos apresentaram uma tend√™ncia de associa√ß√£o (P=0,05) com decl√≠nio cognitivo na DP. Outras variantes do BDNF e outros genes podem estar envolvidos na ocorr√™ncia dos efeitos colaterais da levodopa

    Aspectos gen√©ticos, ambientais e suas intera√ß√Ķes na suscetibilidade e farmacogen√©tica da doen√ßa de Parkinson

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    A doen√ßa de Parkinson (DP) √© a segunda doen√ßa neurodegenerativa mais frequente na esp√©cie humana. A etiologia da DP √© multifatorial, com muitos fatores ambientais e gen√©ticos atuando em conjunto para sua determina√ß√£o. Ao n√≠vel patol√≥gico ela caracteriza-se pela destrui√ß√£o seletiva de neur√īnios dopamin√©rgicos da substantia nigra pars compacta e pelo ac√ļmulo de corpos de Lewy no c√©rebro. Em aproximadamente 90% dos casos da DP, a suscetibilidade parece ser determinada por variantes comuns no genoma que podem interagir com o ambiente. Dentre os fatores ambientais que modulam o risco para a DP est√£o: uso de pesticidas, exposi√ß√£o ocupacional a t√≥xicos, consumo de caf√© e cigarro. A variabilidade na resposta √† principal medica√ß√£o da DP, a levodopa, parece tamb√©m estar relacionada √† gen√©tica do indiv√≠duo. Dessa forma, o presente trabalho teve como objetivo a melhor compreens√£o dos fatores gen√©ticos e suas intera√ß√Ķes com o ambiente envolvidos na suscetibilidade √† DP e no tratamento com levodopa. Pacientes com DP e seus controles foram recrutados no ambulat√≥rio de dist√ļrbios do movimento e no ambulat√≥rio de medicina interna do Hospital de Cl√≠nicas de Porto Alegre e da Universidade Federal de Ci√™ncias da Sa√ļde de Porto Alegre, respectivamente. Os resultados obtidos foram organizados em cinco artigos. No primeiro estudo, foram considerados oito polimorfismos previamente associados √† DP. Na nossa popula√ß√£o, os indiv√≠duos que possu√≠am sete ou mais alelos de risco desses polimorfismos apresentaram um odds ratio de 2,54 quando comparados a quem possu√≠a seis alelos ou menos (95% IC 1,66-3,89; P = 1,80E‚ąí05). Esse ponto de corte foi escolhido porque o n√ļmero m√©dio de alelos de risco na amostra foi 7. No segundo artigo, portadores do gen√≥tipo TT do polimorfismo rs1021463 e dos gen√≥tipos TT ou GT do polimorfismo rs30196 do gene SV2C apresentaram um maior risco a DP quando expostos ocupacionalmente a t√≥xicos, quando comparado a n√£o-expostos (respectivamente, OR 2,53; 95% IC 1,33-4,69; Pintera√ß√£o = 0,008 e OR 2,30; 95% IC 1,21-4,36; Pintera√ß√£o = 0,033). O terceiro artigo mostra uma associa√ß√£o em que fumantes com o hapl√≥tipo T- n√£o G -T do transportador ABCB1 apresentaram menor risco a DP quando comparados a portadores do 9 hapl√≥tipo C-G-C (OR 0,34, 95% IC 0,15-0,72; Pintera√ß√£o = 0,012). No quarto trabalho, foi constatada uma intera√ß√£o entre o gene NOS1 e a cafe√≠na modulando o risco da DP (OR 0,24; 95% IC 0,10-0,54; Pintera√ß√£o = 0,0002). O √ļltimo artigo trata da farmacogen√©tica da levodopa, em que foi proposto um modelo com vari√°veis gen√©ticas, biol√≥gicas e farmacol√≥gicas que explicou 23% da variabilidade na dose (F = 11,54; P < 0,000001). Observou-se uma redu√ß√£o da m√©dia de dose em aproximadamente 76 mg/dia por cada alelo C nos gen√≥tipos do polimorfismo rs30196 do gene SV2C. Estes trabalhos enriqueceram o conhecimento da variabilidade da DP tanto em aspectos de suscetibilidade quanto farmacogen√©tica. Os dados obtidos ser√£o importantes na continua√ß√£o das pesquisas para identificar biomarcadores para preven√ß√£o e tratamento da DP.Parkinson‚Äôs disease (PD) is the second most common neurodegenerative disease in humans. PD etiology is multifactorial, due to several environmental and genetic factors. Pathologically, it is characterized by a selective destruction of dopaminergic neurons in substantia nigra pars compacta and by the accumulation of Lewy bodies in brain. In approximately 90% of PD cases, susceptibility seems to be driven by common variants in the genome that might interact with the environment. Among environmental factors that modulate PD risk, pesticides, occupational exposure to toxics, smoking and coffee consumption were identified. The variability in patients‚Äô response to the main medication of PD, levodopa, seems also to be related to genetics. Therefore, the present work had the objective to understand the genetic factors and their interaction with the environment involved in PD susceptibility and in the treatment with levodopa. Patients and controls were recruited at the movement disorders ambulatory and at the internal medicine ambulatory at the Hospital de Cl√≠nicas de Porto Alegre and at Universidade Federal de Ci√™ncias da Sa√ļde de Porto Alegre respectively. The main results obtained were organized in five manuscripts. In the first, eight polymorphisms previously associated with PD were considered. In our population, individuals with 7 or more risk alleles presented an odds ratio of 2.54 for PD when compared to those with 6 or less alleles (95% CI 1.66-3.89; P = 1.80E‚ąí05). This cut off was chosen because the average number of risk alleles in the sample was 7. In the second manuscript, SV2C rs10214163 TT genotype carriers and SV2C rs30196 TT/GT genotypes carriers showed a higher PD risk in subjects exposed to environmental toxics compared to those not exposed (respectively, OR 2.53; 95% CI 1.33-4.69; Pinteraction = 0.008 and OR 2.30; 95% CI 1.21-4.36; Pinteraction = 0.033). The third manuscript shows the association between ABCB1 T-non G-T haplotype and smoking (OR 0.34, 95% CI 0.15-0.72; Pinteraction = 0.012). In the fourth manuscript, an interaction between NOS1 gene and caffeine, modulating PD risk, was observed (OR 0.24; 95% CI 0.10-0.54; Pinteraction = 0.0002). The last manuscript reports a 11 model with genetic, biological and pharmacological variants in response to levodopa. This model explained 23% of dose variability (F = 11.54; P < 0.000001). The presence of each rs30196 C allele reduced the average dose in approximately 76 mg/day. All these work enriched the knowledge of the variability of PD in both susceptibility and pharmacogenetic areas. The data obtained will be important to identify biomarkers for disease prediction and treatment

    Influência de variantes do gene do fator neurotrófico derivado do cérebro e da apolipoproteína e no déficit cognitivo da doença de Parkinson

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    A doen√ßa de Parkinson (DP) possui preval√™ncia de 3,3% na popula√ß√£o brasileira. Essa doen√ßa √© caracterizada por sintomas motores caracter√≠sticos. Os pacientes com DP apresentam tamb√©m sintomas n√£o motores como o d√©ficit cognitivo. Esse sintoma prejudica a qualidade de vida dos pacientes e pode progredir ao longo do tempo. O d√©ficit cognitivo n√£o possui uma neuropatologia bem compreendida. V√°rios estudos sugerem que a etiologia desse sintoma seja devida pelo menos em parte ao perfil gen√©tico do paciente. No presente trabalho, foram analisados dois genes envolvidos com a neuroplasticidade sin√°ptica, o BDNF e a APOE e sua poss√≠vel associa√ß√£o com a ocorr√™ncia de d√©ficit cognitivo na Doen√ßa de Parkinson. O BDNF √© relacionado √† sobreviv√™ncia, diferencia√ß√£o e manuten√ß√£o dos neur√īnios, e tamb√©m com a forma√ß√£o de mem√≥ria. Um polimorfismo na regi√£o codificante (Val66Met) nesse gene est√° relacionado a uma menor secre√ß√£o de prote√≠na. A APOE interage com neur√īnios, promovendo sinaptog√™nese, crescimento axonal, reparo de nervos e na preven√ß√£o de morte neuronal. Essa lipoprote√≠na possui tr√™s isoformas codificadas pelos alelos őĶ2, őĶ3 e őĶ4. O alelo őĶ4 foi previamente associado a dem√™ncia na DP em alguns estudos. Um total de 163 pacientes com DP idiop√°tica foram diagnosticados e recrutados no ambulat√≥rio de Dist√ļrbios do Movimento no Hospital de Cl√≠nicas de Porto Alegre. Todos os indiv√≠duos foram genotipados para os polimorfismos dos genes BDNF e APOE por t√©cnicas baseadas em PCR. A escala do Mini Mental Test Examination (MMSE) foi utilizada para definir a ocorr√™ncia de d√©ficit cognitivo Pacientes portadores do alelo 66Met do gene do BDNF apresentaram maior preval√™ncia de d√©ficit cognitivo (p=0,006; PR=1,52; IC=95% [1,12-2,05]). Em rela√ß√£o a APOE, n√£o foi encontrada associa√ß√£o do alelo őĶ4 com d√©ficit cognitivo na DP (p=0,393; PR=1,15; IC=95% [0,84-1,58]). Esses resultados corroboram trabalhos anteriores que descrevem associa√ß√Ķes gen√©ticas com d√©ficit cognitivo na DP e sugerem que o BDNF possa ter um importante papel na patog√™nese do d√©ficit cognitivo na doen√ßa de Parkinson.Parkinson's disease (PD) has a prevalence of 3.3% in the Brazilian population. This disease is characterized by motor symptoms. However patients with this disease also present non-motor symptoms as cognitive impairment. This symptom greatly affects functioning and patient`s quality of life. The Cognitive impairment neuropathology is still not elucidated. Several studies suggested that its etiology is due, at least in part, to patient`s genetic profile. In the present study, two genes related to neuroplasticity were investigated, BDNF and APOE. BDNF is related to survival, differentiation and neuron maintenance, as well as memory formation. A coding polymorphism in this gene (Val66Met) is related to impaired secretion of the BDNF protein. APOE interacts with neurons, promoting synaptogenesis stimulation, axonal growth, nerve repair and prevent neuronal death. This protein has three isoforms coded by the őĶ2, őĶ3 and őĶ4 alleles. Allele őĶ4 was previously associated with dementia in Parkinson's disease in studies. A total of 163 patients were diagnosed and recruited at the Movement Disorders clinics at "Hospital de Cl√≠nicas de Porto Alegre. All individuals were genotyped for polymorphisms in BDNF and APOE by PCR based methods. Cognitive impairment diagnosis was based on the Mini Mental Test Examination (MMSE). Carriers of BDNF 66Met allele presented a higher prevalence of cognitive impairment (p=0.006, PR=1.52, 95% CI [1.12-2.05]). However, no association was observed for őĶ4 carriers with cognitive impairment (p=0.393, PR=1.15, 95% CI [0.84-1.58]). These results extend previously described genetic associations with cognitive impairment in PD and suggest that BDNF might play a role in the pathogenesis of cognitive impairment in Parkinson's disease
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