A doença de Parkinson é uma doença neurodegenerativa, cujo aparecimento pode estar ligado a mutações ou alterações na expressão do gene SNCA, o qual codifica a proteína a-sinucleína. A expressão do gene em Saccharomyces cerevisiae produz fenótipos típicos de células parkinsonianas, como a formação de corpos de Lewy, que levam a um aumento na produção de espécies reativas de oxigênio (ROS) na mitocôndria. Assim, a produção de melatonina, um antioxidante natural, poderia ser um possível tratamento para a expressão do de SNCA. Aqui, mostramos que a produção de a-sinucleína é prejudicial ao crescimento e à respiração de leveduras, fenótipo semelhante ao desafio com o agente oxidante menadiona. A produção ou suplementação farmacológica de melatonina possui efeito protetor, conferindo vantagem em meio seletivo para atividade respiratória, melhorando a função mitocondrial de leveduras parkinsonianas. Nossos resultados apontam para um papel promissor da melatonina na proteção das células contra danos oxidativos da produção de a-sinucleína em leveduras. / Parkinson\'s disease is a progressive neurodegenerative disorder often linked to mutation or expression alteration of the SNCA gene that encodes the a-synuclein (a-syn) protein. SNCA expression in Saccharomyces cerevisiae leads to deposition Lewy bodies that increase mitochondrial reactive oxygen species (ROS) production, one of the hallmarks of the disease. Hence, a possible treatment would be ROS neutralization through natural antioxidants, such as melatonin. Here we show that a-syn production is detrimental to yeast growth and respiration, similar to the phenotype observed during menadione oxidative challenge. Melatonin production or pharmacological supplementation confers antioxidant protection against oxidative agents, improving mitochondrial respiratory parameters from parkinsonian yeast grown with melatonin. Our studies point out to a promising role of melatonin in protecting yeast against a-syn and other species oxidative damage.

O déficit de controle postural é impactante em indivíduos com doença de Parkinson (DP), nesse sentido, a aprendizagem de tarefas que o envolvam é fundamental para esses indivíduos. Recentemente, estudos têm mostrado que indivíduos com DP são capazes de aprender tarefas com demanda de controle postural, no entanto, o intervalo de retenção destes estudos é muito curto considerando-se uma doença neurodegenerativa. Outra questão que se coloca é, em aprendendo tarefas de demanda de controle postural, poderia haver diminuição da instabilidade postural, porém ainda não existem evidências concretas para responder esse questionamento. Nesse sentido, o objetivo do presente estudo foi investigar a aprendizagem de tarefas que envolvam demanda de controle postural em ambiente de realidade virtual em indivíduos com DP quando comparados com idosos saudáveis em curto e longo prazo, além de verificar seu impacto na cognição e no controle postural dos mesmos. A amostra foi composta por 28 sujeitos, sendo 14, com DP idiopática no grupo experimental (GE) [64.28±6.35 anos; escala de Hoehn e Yahr modificada = 14.28% dos sujeitos 1; 14.28%, 1.5; 7.14%, 2; 21.42%, 2.5; 42.85%, 3; Montreal Cognitive Assessment (MoCA) = 22.42±3.41; e Mini Balance Evaluation Systems Test (MiniBEStest) = 20.78±6.54]. Foram incluídos também 14 idosos saudáveis no grupo controle (GC) [69.71±5.91 anos; MoCA = 23.64±3.17; e MiniBESTest = 27.35±2.67]. Foram realizadas 13 sessões com duração de uma hora, 2x/semana por sete semanas, no período on da medicação para a reposição dopaminérgica, sendo a primeira considerada pré-teste e a última, pós-teste. A prática consistiu em jogar quatro jogos do sistema Kinect, 5 tentativas por jogo. Foram realizados dois testes de retenção, sendo o primeiro após uma semana e o segundo após um mês. A avaliação da cognição, através da MoCA, e do controle postural, através do MiniBESTest, foi realizada antes, imediatamente após e um mês após a fase de aquisição. Indivíduos com DP foram capazes de aprender tarefas com demanda de controle postural, havendo retenção a curto e longo prazo, apesar do desempenho apresentar-se inferior aos idosos neurologicamente saudáveis. Além disso, aprender as tarefas propostas levou a melhora da cognição, especificamente na memória e nos aspectos reativos do controle postural de idosos e indivíduos com DP, além da melhora da estabilidade de marcha somente dos idosos / Postural control deficits are striking in individuals with Parkinson\'s disease (PD), making the learning of postural control tasks crucial for these individuals. Recent studies have shown that PD patients are able to learn tasks with postural control demand; however, the retention interval found in these studies was quite short due to the nature of this neurodegenerative disease. Hence, in the learning process of high demand postural control tasks, is there a decrease in PD patients\' postural instability? Concrete data are needed to answer this question. Therefore, the purpose of this study was to investigate the learning of tasks involving a high demand for postural control in a virtual reality environment in individuals with PD when compared to healthy elderly. The learning process was investigated through both short- and long-term retention. The secondary purpose was to verify the learning process\'s impact on both cognition and postural control. The sample included 28 participants: 14 with idiopathic PD in the Experimental Group (EG) [64.28±6.35 years; Hoehn e Yahr modified scale = 14.28% 1; 14.28%, 1.5; 7.14%, 2; 21.42%, 2.5; 42.85%, 3; Montreal Cognitive Assessment (MoCA) = 22.42±3.41; and Mini Balance Evaluation Systems Test (MiniBEStest) = 20.78±6.54] and fourteen healthy elderly in the Control Group (CG) [69.71±5.91 years; MoCA = 23.64±3.17; e MiniBESTest = 27.35±2.67]. Thirteen one-hour sessions were performed two x/week for seven weeks, which was the on-medication period for dopaminergic replacement. The first session was considered as the pre-test, and the last session was considered as the post-test. The practice consisted of playing four Kinect system games, with five trials per game. Two retention tests were performed, with the first occurring after one week and the second occurring one month after the end of the acquisition phase. The assessment of cognition through MoCA and postural control through MiniBESTest were performed before, immediately after and one month after the acquisition phase. Individuals with PD learned tasks with a high demand for postural control and had both short- and long-term retention, despite their inferior performance compared to the neurologically healthy elderly. In addition, learning the proposed tasks led to an improvement in cognition, specifically in memory, and in the reactive aspects of postural control in the elderly and individuals with PD, as well as gait stability only in the elderly

Avaliamos a orientação da atenção visual de pacientes com Doença de Parkinson (DP), idosos e jovens saudáveis. Foram feitos cinco experimentos de Tempo de Reação (TR) e de Julgamento de Ordem Temporal (JOT), nos quais se avaliaram a atenção automática e voluntária e a percepção de ordem temporal. Os pacientes com DP apresentaram déficits em relação aos idosos na atenção voluntária, na percepção de ordem temporal e na flexibilidade mental, mas tiveram resultados semelhantes aos idosos na avaliação da atenção automática. A correlação entre os valores do TR e do JOT foi significativa entre os experimentos de TR e JOT, o que evidencia que os déficits dos DP e idosos têm origem num mecanismo em comum: a atenção. / We investigated the orienting of visual attention in patients with Parkinson?s disease (PD), healthy elderly and young subjects. Five Reaction Time (RT) and Temporal Order Judgment (TOJ) experiments were performed in order to evaluate automatic and voluntary attention and perception of temporal order. The PD patients exhibited a deficit when compared to the healthy elderly subjects in voluntary attention, perception of temporal order and mental flexibility, but had similar results in the automatic attention task. The correlation between the values obtained in RT and TOJ experiments was significant, which points towards a common mechanism underlying deficits of PD patients and effects of aging: attention.

Distúrbios de equilíbrio são sintomas da Doença de Parkinson (DP) que contribuem significativamente para a perda da independência e funcionalidade. Com a evolução da DP os distúrbios se agravam e prejudicam a qualidade de vida dos pacientes. A fisioterapia é uma ferramenta importante para o tratamento dessas alterações motoras da DP sendo indicada como recurso auxiliar ao tratamento medicamentoso. Evidências demonstram que o uso de pistas externas acarreta em melhoras motoras expressivas da marcha, embora os mecanismos pelos quais essas melhoras ocorrem, ainda permanecem sem esclarecimento. Poucos estudos investigam treinamentos para melhora do equilíbrio e pouco se sabe em relação ao uso de pistas externas auditivas para o treinamento do mesmo. O objetivo do estudo é verificar a eficácia de um programa de treinamento motor para melhora do equilíbrio associado a pistas auditivas e suas repercussões na marcha e sintomas não motores da DP como: fadiga, depressão e qualidade de vida. Para tal, foi avaliado por um examinador cego o equilíbrio e a marcha de 36 pacientes com DP, idade média de 65.91 anos (DV = 6,51), nos estágios 2 a 3 da Hoehn and Yahr Classification (HY), sendo 12 sujeitos controle pareados por idade e sexo, antes e depois de 10 sessões de treinamento (5 semanas com 45 minutos de duração). O desempenho do equilíbrio foi avaliado por meio do BERG test (BT) e Postural Stress Test (PST). O desempenho da marcha foi avaliado com e sem distrator por meio de do teste de agilidade (AG), teste Time Up Go (TUG) e a velocidade da marcha, a partir da posição sentada, num percurso de 21 metros com obstáculos em deslocamento anterior (DA). Os pacientes realizaram ainda avaliação da independência para as AVDs e desempenho motor por meio da seção II e III da UPDRS e da Qualidade de vida através da Parkinsons Disease Quality of Life (PDQL). Foram aplicadas as escalas de Fadiga (FSS) 36, Inventário de Depressão de Beck todos os pacientes foram esclarecidos e assinaram o termo de consentimento. Após a avaliação inicial, os pacientes foram distribuídos em dois grupos por ordem de chegada de acordo com os critérios de inclusão. Um dos grupos experimentais (GEP), realizou o programa motor para marcha e equilíbrio associados ao uso de pistas rítmicas auditivas e o outro grupo realizou o mesmo programa o sem pistas (GESP). O grupo controle (GC) permaneceu sem atividade física no mesmo período recebendo apenas orientações gerais. Os resultados mostram que, após o treinamento motor acoplado ao uso das pistas auditivas rítmicas (GEP) houve melhora significativa do equilíbrio do em relação ao treinamento controle (GESP) na pontuação média do BERG (p< 0,00), PSTQ (p< 0,00) PSTO (p< 0,00). Isso indica que o uso das pistas auditivas rítmicas proporciona melhora significativa do equilíbrio. Para os demais aspectos avaliados como os sintomas não motores e a marcha, foi encontrada diferença significativa de avaliação para ambos os grupos experimentais (GEP e GESP), mostrando que o treinamento motor é eficaz para esses aspectos. Porém não houve efeito de grupo e mostrando que a melhora do equilíbrio com o uso das pistas, não se repercutiu para a marcha. Provavelmente a melhora da marcha se deu por meio dos aspectos mais gerais do treinamento como: a melhora da força muscular, flexibilidade, agilidade e endurance. O grupo controle não apresentou nenhuma modificação significativa em relação aos resultados. Conclui-se que o treinamento motor acoplado ao uso das pistas auditivas rítmicas proporciona melhora do equilíbrio e maior eficácia dos ajustes compensatórios e antecipatórios na DP. A melhora do equilíbrio obtida com o treinamento associado a pistas rítmicas não se repercute para a marcha e aspectos não motores. / Balance disturbances are DP symptoms which contribute significantly to the loss of independence and functionality. As DP evolves, disturbances worsen and compromise the patients´ quality of life. Physiotherapy is an important resource for treating such motor alterations as well as an additional to pharmaco approach. Evidences have shown that the use of external cues can bring important motor recovery to the gait, although the mechanisms, in which these recoveries occur, have no explanations yet. Few studies investigate balance improvement training as well as the use of auditory external cues as a resource for training balance itself. So, the aim of the present study is to verify the efficiency of a motor training program to improve balance related to auditory cues and its effects in gait and no motors aspects in DP like: fatigue, depression and life quality. Thus, a blinded examiner carried out an assessment in the balance and gait of 36 DP patients, with a mean age of 65.91years (DV=6, 51), at stages 2 to 3 of the Hoehn and Yahr Classification (HY). The subjects were matched by age and sex, before and after 10 training sessions (5 weeks 45 minutes sessions). Balance performance was assessed using the BERG Test (BT) and Postural Stress Test (PST). Performance in gait was assessed, with and without concurrent tasks , through agility test (AG), TIME UP GO (TUG) test and gait velocity, starting in sit position, with 21 meters trajectory with obstacles at a anterior displace (DA). Patients were also assessed for independence to DLA (Daily Life Activities) and motor performance using section II and III of the UPDRS and for Quality of Life using the Parkinsons disease Quality of Life (PDQL). Fatigue Scale (FSS) 36 were carried out, and for emotional state Becks Depression Inventory (BDI); evey patient was elucidated and had to sign a permission term. After an initial assessment, patients were divided in two groups, for order of arrival, according inclusion rules. Assigned into one of 3 groups: one of the experimental groups, receiving motor training to gait and balance, associated auditory rhythmical cues (ET); the other, performed the same motor training without cues (MT). The control group received general orientations but remained without physical activity. The results show that there was significant recovery of balance after a motor training connected to the use of rhythmical and auditory cues (GEP) in relation to the control training (GESP) BERG average score (p<0,00), PSTQ (p<0,00) PSTO (p<0,00). It means that: rhythmical and auditory cues improve balance. In relation to no motors symptoms and gait, significant assessment difference was shown to both experimental groups (GEP and GESP), concluding that motor training is efficient to these aspects. But, there was no group effect and, the improvement with the use of the cues, didnt reflect directly in the gait. Probably, the improvement of the gait occurred through general aspects of the training like: muscular strength improvement, flexibility, agility and endurance. The control group presented no significant changes. Conclusion: motor training connected to rhythmical and auditory cues improves balance and a greater efficiency of the compensators and anticipators adjusts in DP. Balance improvement obtained with training related to rhythmical cues dont work to gait and no motor aspects.

A doença de Parkinson (DP) é uma doença neurodegenerativa caracterizada pela progressiva depleção dos neurônios dopaminérgicos da substância negra (pars compacta). A DP não ocasiona apenas uma desordem motora, mas também pode provocar uma disautonomia cardiovascular. A DP com sintomas similares aos que ocorrem em humanos pode ser experimentalmente induzida em ratos e camundongos com a administração das neurotoxinas 1-metil-1-4-fenil-1,2,3,6-tetrahidropirimidina (MPTP), 6-hidroxidopamina (6-OHDA) e rotenona. Mais, na década de 90, camundongos transgênicos que expressam altos níveis de alfa-sinucleína mutante humana têm sido produzidos e utilizados para investigar a possível relação entre a agregação da proteína alfa-sinucleína e a DP, uma vez que em humanos, a alta expressão dessa proteína está relacionada ao desenvolvimento do parkinsonismo associado à desnervação cardíaca simpática. No entanto, a desnervação cardíaca e suas conseqüências no miocárdio na DP não estão claramente caracterizadas, pois na literatura os métodos quantitativos empregados para tal finalidade têm sua confiabilidade e acurácia questionáveis. Desta forma, avaliou-se, no modelo de indução neurotóxico (MPTP), o miocárdio de camundongos C57/BL aplicando-se métodos morfoquantitativos tridimensionais (estereológicos). Neste trabalho, observamos que o volume da parede ventricular, o volume e a densidade de volume do interstício cardíaco foram, respectivamente, 0,8%, 5,3% e 2,4% maior no grupo MPTP. O volume do lúmen ventricular, o volume ventricular, o volume das fibras musculares cardíacas e a sua densidade de volume foram, respectivamente, 11,7%, 0,9%, 2,3% e 1,7% maior no grupo controle. O número total de núcleos de cardiomiócitos foi 14,8% menor no grupo MPTP bem como o número total de cardiomiócitos que foi 19% menor também neste grupo. Houve diferença estatística significativa entre os grupos para o parâmetro número de cardiomiócitos. Não houve, porém, diferença estatística significativa para os outros parâmetros avaliados. / Parkinson´s disease (PD) is a neurodegenerative disorder mostly characterised by a profound reduction of dopamine in the striatum due to a dramatic loss of dopaminergic neurons in the substantia nigra (pars compacta). The disease is not only characterised by a motor disorder but also present cardiovascular dysautonomia. The disease has been chemically induced in rats and mice using neurotoxins such as 1-metyl-1-4-phenyl-1,2,3,6-tetrahydropyrimidina (MPTP), 6-OHDA and rotenone. In the nineties, transgenic &alpha;-synuclein mice have recently been used as a model of PD and alpha-synuclein aggregation, because the overexpression of this protein is related to the development of parkinsonism associated to the sympathetic cardiac denervation. Although, the cardiac denervation in PD and its consequences in myocardium is not well defined because the literature reports no reliable quantitative methods. Therefore, the myocardium of the C57/BL mice was investigated in the neurotoxin animal model (MPTP) applying tridimensional morphoquantitative methods (stereological). In this study, we observed an increase of 0,8%, 5,3% and 2,4% in ventricular wall volume, in cardiac interstitial volume and in cardiac interstitial volume density, respectively, in the MPTP group. The lumen ventricular volume, the ventricular volume, the cardiac muscle fibre and their volume density were, respectively, 11,7%, 0,9% , 2,3% and 1,7% larger in control group. The total number of cardiomyocyte nuclei was 14,8% lower in MPTP group as well as the total number of cardiomyocyte that was 19% lower for this group too. Significant difference was observed between the groups to the total number of cardiomyocyte. No significant difference, however, was detected for the others estimated parameters.

O déficit de controle postural é impactante em indivíduos com doença de Parkinson (DP), nesse sentido, a aprendizagem de tarefas que o envolvam é fundamental para esses indivíduos. Recentemente, estudos têm mostrado que indivíduos com DP são capazes de aprender tarefas com demanda de controle postural, no entanto, o intervalo de retenção destes estudos é muito curto considerando-se uma doença neurodegenerativa. Outra questão que se coloca é, em aprendendo tarefas de demanda de controle postural, poderia haver diminuição da instabilidade postural, porém ainda não existem evidências concretas para responder esse questionamento. Nesse sentido, o objetivo do presente estudo foi investigar a aprendizagem de tarefas que envolvam demanda de controle postural em ambiente de realidade virtual em indivíduos com DP quando comparados com idosos saudáveis em curto e longo prazo, além de verificar seu impacto na cognição e no controle postural dos mesmos. A amostra foi composta por 28 sujeitos, sendo 14, com DP idiopática no grupo experimental (GE) [64.28±6.35 anos; escala de Hoehn e Yahr modificada = 14.28% dos sujeitos 1; 14.28%, 1.5; 7.14%, 2; 21.42%, 2.5; 42.85%, 3; Montreal Cognitive Assessment (MoCA) = 22.42±3.41; e Mini Balance Evaluation Systems Test (MiniBEStest) = 20.78±6.54]. Foram incluídos também 14 idosos saudáveis no grupo controle (GC) [69.71±5.91 anos; MoCA = 23.64±3.17; e MiniBESTest = 27.35±2.67]. Foram realizadas 13 sessões com duração de uma hora, 2x/semana por sete semanas, no período on da medicação para a reposição dopaminérgica, sendo a primeira considerada pré-teste e a última, pós-teste. A prática consistiu em jogar quatro jogos do sistema Kinect, 5 tentativas por jogo. Foram realizados dois testes de retenção, sendo o primeiro após uma semana e o segundo após um mês. A avaliação da cognição, através da MoCA, e do controle postural, através do MiniBESTest, foi realizada antes, imediatamente após e um mês após a fase de aquisição. Indivíduos com DP foram capazes de aprender tarefas com demanda de controle postural, havendo retenção a curto e longo prazo, apesar do desempenho apresentar-se inferior aos idosos neurologicamente saudáveis. Além disso, aprender as tarefas propostas levou a melhora da cognição, especificamente na memória e nos aspectos reativos do controle postural de idosos e indivíduos com DP, além da melhora da estabilidade de marcha somente dos idosos / Postural control deficits are striking in individuals with Parkinson\'s disease (PD), making the learning of postural control tasks crucial for these individuals. Recent studies have shown that PD patients are able to learn tasks with postural control demand; however, the retention interval found in these studies was quite short due to the nature of this neurodegenerative disease. Hence, in the learning process of high demand postural control tasks, is there a decrease in PD patients\' postural instability? Concrete data are needed to answer this question. Therefore, the purpose of this study was to investigate the learning of tasks involving a high demand for postural control in a virtual reality environment in individuals with PD when compared to healthy elderly. The learning process was investigated through both short- and long-term retention. The secondary purpose was to verify the learning process\'s impact on both cognition and postural control. The sample included 28 participants: 14 with idiopathic PD in the Experimental Group (EG) [64.28±6.35 years; Hoehn e Yahr modified scale = 14.28% 1; 14.28%, 1.5; 7.14%, 2; 21.42%, 2.5; 42.85%, 3; Montreal Cognitive Assessment (MoCA) = 22.42±3.41; and Mini Balance Evaluation Systems Test (MiniBEStest) = 20.78±6.54] and fourteen healthy elderly in the Control Group (CG) [69.71±5.91 years; MoCA = 23.64±3.17; e MiniBESTest = 27.35±2.67]. Thirteen one-hour sessions were performed two x/week for seven weeks, which was the on-medication period for dopaminergic replacement. The first session was considered as the pre-test, and the last session was considered as the post-test. The practice consisted of playing four Kinect system games, with five trials per game. Two retention tests were performed, with the first occurring after one week and the second occurring one month after the end of the acquisition phase. The assessment of cognition through MoCA and postural control through MiniBESTest were performed before, immediately after and one month after the acquisition phase. Individuals with PD learned tasks with a high demand for postural control and had both short- and long-term retention, despite their inferior performance compared to the neurologically healthy elderly. In addition, learning the proposed tasks led to an improvement in cognition, specifically in memory, and in the reactive aspects of postural control in the elderly and individuals with PD, as well as gait stability only in the elderly

The aetiology of Parkinson's disease (PD) is still unclear. Research findings suggest that both environmental and genetic factors may contribute to its development. The interactions between genes and the environment might exist and play a key role. Cigarette smoking was found to be one of the few factors exhibiting a protective effect. If chemical compounds found in cigarette smoke influence PD risk, the difference in the ability of certain individuals in metabolising these substances might alter their susceptibility to the risk of developing PD. Many metabolic enzyme genes exhibit polymorphic traits with alteration of gene function. These might be associated with an altered susceptibility of individuals to PD. Few studies have examined the hypothesis that metabolic enzyme gene polymorphisms might modulate the effect of smoking on PD risk. However, it is crucial to consider these potential interactions when we try to elucidate the aetiology of PD. Even if each factor only contributes a slight variation and influences a small portion of the whole population, non-linear and unpredictable interactions may account for a high proportion of the aetiological fraction. Previous studies have not been strictly designed to examine the interactions between smoking and metabolic enzyme genetic polymorphisms. These studies have not been able to elucidate the extent of the interaction. Therefore, this PhD project attempted to examine whether genetic factors, operating in the phase one and phase two metabolic pathways, interact with smoking to influence the development of PD. This is the first genetic epidemiological study of PD specifically addressing this issue. The research aids in further understanding the aetiology of PD and may be useful for identifying people at higher risk. A case-only design was chosen for this project for two reasons: first, PD is a relatively rare disease and the case-only design is much more efficient at detecting gene-environment interactions; second, the PD cases for the project were recruited over the past few years and represent a prevalence series, for which an appropriate comparison group for the cases is difficult to identify and recruit. In a case-only study, only cases are used to investigate the multiplicative effects of the exposures and susceptible genotypes of interest, while non-case subjects (traditionally controls) are solely used to test the independence between the exposure and the susceptible genotype. Therefore, this approach avoids the challenges of control selection, a major limitation inherent in the case-control approach. This thesis comprised of three independent studies: the first study investigated the interactions between genetic polymorphisms of GSTM1, P1, T1 and Z1 and smoking in PD; the second study examined the interactions between genetic polymorphisms of CYP2E1 and smoking in PD; and the third study examined the interactions between genetic polymorphisms of CYP2D6 and smoking in PD. The first two studies recruited 400 white Caucasian PD cases from both hospital wards and private neurology clinics (230 men and 170 women). The third study further included 142 white Caucasian PD cases newly recruited from the same sources (542 in total, 321 men, and 221 women). The mean age of cases was 67 years with the average onset age at 60 years. GSTM1, GSTP1, GSTT1, GSTZ1 AND CYP2E1 genotyping processes were performed using protocols previously published with minor modification, whereas CYP2D6 genotyping methods were mainly developed by me with assistance from associate supervisor Dr. George Mellick. Reliability and validity of the PCR and RFLP methods were assessed through re-conducting the genotype assays using at least a 10% sample of our DNA samples. The results for all re-assessments were 100% concordant. Crude bivariate analyses were adjusted for potential confounding effects of the variables, including age at onset, gender, family history of PD and pesticide exposures. Among our unaffected, aged subjects (mean age: 63.9 years, sd: 11.4 years), the genotype frequencies at each locus were similar to those reported in other Caucasian populations. The first study showed that the proportion of carriers of the GSTP1-114Val allele (mutant) increased with increasing smoking dose from 0 to > 30 pack-years. Homozygotes of the 114Ala allele (wild-type) decreased with increasing smoking dose (trend test: p=0.02). This trend existed both in male and female cases. This dose-effect relationship was most significant in the group of cases with late-onset PD (i.e., age at onset > 55 years) with the ORicase-only values of 1.88 (95%CI: 0.65-5.48) and 2.63 (95%CI: 1.07-6.49) for > 0-10 and > 10 pack-years, respectively. No similar trend was found among our unaffected, aged subjects (p=0.42). Haplotype analyses revealed significant differences for GSTP1 haplotypes between smoking and non-smoking PD cases (ORicase-only for *C haplotype=2.00 (95%CI: 1.11-3.60), p=0.03). In this case, smoking-exposed PD cases were more likely to posses the *C haplotype defined by A to G base-pair transition at nucleotide +313 and C to T base-pair transition at nucleotide +341 (at amino acid level, valine at both positions 105 and 114). The second study found no difference in CYP2E1 genotype frequencies between PD cases who ever smoked compared to those who never smoked (odds ratio for interaction (ORi) = 1.00 (95% CI: 0.39-2.51, p=0.99)). No CYP2E1 gene-smoking interactions were detected in relation to age at onset of PD. The third study found that among cases without regular pesticide exposures, CYP2D6 PMs who smoked more than 5 pack-years had a later mean age at disease onset (68.6 years) than those with extensive metaboliser phenotypes (EMs) (61.1 years, p=0.02) and non-smokers (60.5 years, p=0.01). Analysis of aged subjects without PD confirmed that neither smoking status nor CYP2D6 PM status was associated with age itself. Our data suggest: 1. smoking exposure is independent of GSTM1, P1, T1, Z1 and CYP2E1 genotypes; 2. smoking may be, to some extent, associated with CYP2D6 genotypes; 3. there are no multiplicative interactive effects linking smoking and GSTM1, T1, Z1 or CYP2E1 genotypes with the risk for PD; 4. there is a multiplicative interactive effect between smoking and GSTP1 haplotype - particularly for genotypes carrying the 114Val allele; and 5. there is a multiplicative interactive effect between smoking and CYP2D6 PMs - particularly for people who ever smoked cigarettes more than 5 pack-years. In general, this thesis provides a model for exploring the gene-smoking interactions in PD. Further studies need to consider the recruitment of a large number of population-based and randomly-selected samples and to pay more attention to measurement of environmental exposures. Further studies also need to examine simultaneously the impact of smoking, pesticide exposures and other potential risk factors on PD. These studies will build evidence for interactions contributing to this common neurological movement disorder.

No description available.

Avaliamos a orientação da atenção visual de pacientes com Doença de Parkinson (DP), idosos e jovens saudáveis. Foram feitos cinco experimentos de Tempo de Reação (TR) e de Julgamento de Ordem Temporal (JOT), nos quais se avaliaram a atenção automática e voluntária e a percepção de ordem temporal. Os pacientes com DP apresentaram déficits em relação aos idosos na atenção voluntária, na percepção de ordem temporal e na flexibilidade mental, mas tiveram resultados semelhantes aos idosos na avaliação da atenção automática. A correlação entre os valores do TR e do JOT foi significativa entre os experimentos de TR e JOT, o que evidencia que os déficits dos DP e idosos têm origem num mecanismo em comum: a atenção. / We investigated the orienting of visual attention in patients with Parkinson?s disease (PD), healthy elderly and young subjects. Five Reaction Time (RT) and Temporal Order Judgment (TOJ) experiments were performed in order to evaluate automatic and voluntary attention and perception of temporal order. The PD patients exhibited a deficit when compared to the healthy elderly subjects in voluntary attention, perception of temporal order and mental flexibility, but had similar results in the automatic attention task. The correlation between the values obtained in RT and TOJ experiments was significant, which points towards a common mechanism underlying deficits of PD patients and effects of aging: attention.

A doença de Parkinson é uma doença neurodegenerativa, cujo aparecimento pode estar ligado a mutações ou alterações na expressão do gene SNCA, o qual codifica a proteína a-sinucleína. A expressão do gene em Saccharomyces cerevisiae produz fenótipos típicos de células parkinsonianas, como a formação de corpos de Lewy, que levam a um aumento na produção de espécies reativas de oxigênio (ROS) na mitocôndria. Assim, a produção de melatonina, um antioxidante natural, poderia ser um possível tratamento para a expressão do de SNCA. Aqui, mostramos que a produção de a-sinucleína é prejudicial ao crescimento e à respiração de leveduras, fenótipo semelhante ao desafio com o agente oxidante menadiona. A produção ou suplementação farmacológica de melatonina possui efeito protetor, conferindo vantagem em meio seletivo para atividade respiratória, melhorando a função mitocondrial de leveduras parkinsonianas. Nossos resultados apontam para um papel promissor da melatonina na proteção das células contra danos oxidativos da produção de a-sinucleína em leveduras. / Parkinson\'s disease is a progressive neurodegenerative disorder often linked to mutation or expression alteration of the SNCA gene that encodes the a-synuclein (a-syn) protein. SNCA expression in Saccharomyces cerevisiae leads to deposition Lewy bodies that increase mitochondrial reactive oxygen species (ROS) production, one of the hallmarks of the disease. Hence, a possible treatment would be ROS neutralization through natural antioxidants, such as melatonin. Here we show that a-syn production is detrimental to yeast growth and respiration, similar to the phenotype observed during menadione oxidative challenge. Melatonin production or pharmacological supplementation confers antioxidant protection against oxidative agents, improving mitochondrial respiratory parameters from parkinsonian yeast grown with melatonin. Our studies point out to a promising role of melatonin in protecting yeast against a-syn and other species oxidative damage.