RESUMO
We have studied the association of a null mutation of Glutathione Transferase M1 (GST M1*0/0) with Parkinson's disease (MIM 168600) in a Chilean population with a strong Amerindian genetic component. We determined the genotype in 349 patients with idiopathic Parkinson's disease (174 female and 175 male; 66.84+/-10.7 years of age), and compared that to 611 controls (457 female and 254 male; 62+/-13.4 years of age). A significant association of the null mutation in GST M1 with Parkinson's disease was found (p=0.021), and the association was strongest in the earlier age range. An association of GSTM1*0/0 with Parkinson's disease supports the hypothesis that Glutathione Transferase M1 plays a role in protecting astrocytes against toxic dopamine oxidative metabolism, and most likely by preventing toxic one-electron reduction of aminochrome.
Assuntos
Predisposição Genética para Doença/genética , Glutationa Transferase/genética , Estresse Oxidativo/genética , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Astrócitos/enzimologia , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Chile/etnologia , Citoproteção/genética , Análise Mutacional de DNA , Dopamina/metabolismo , Feminino , Testes Genéticos , Genótipo , Humanos , Indígenas Sul-Americanos/etnologia , Indígenas Sul-Americanos/genética , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/etnologiaRESUMO
Pathogenic substitutions in the leucine-rich repeat kinase 2 protein (Lrrk2), R1441G and G2019S, are a prevalent cause of autosomal dominant and sporadic Parkinson's disease in the Northern Spanish population. In this study we examined the frequency of these two substitutions in 166 Parkinson's disease patients and 153 controls from Chile, a population with Spanish/European-Amerindian admixture. Lrrk2 R1441G was not observed, however Lrrk2 G2019S was detected in one familial and four sporadic Parkinson's disease patients. These findings suggest Lrrk2 G2019S may play an important role in Parkinson's disease on the South American Continent and further studies are now warranted.
Assuntos
Predisposição Genética para Doença , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Idade de Início , Chile/epidemiologia , Análise Mutacional de DNA , Feminino , Frequência do Gene , Haplótipos , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da PolimeraseRESUMO
To explore the possible influence of heavy metal mining on incidence of Parkinson's disease (PD), global DNA methylation was assessed in blood samples from a population of PD patients (n = 45) and control subjects (n = 52) in Antofagasta neighborhood, a Chilean city built for exclusive use of mining companies. Comparisons were made with PD subjects (n = 52) and control subjects (n = 59) from Santiago Chile, a city having little association with mining. All subjects were assessed by two neurologists and PD diagnosis was based on UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria. From blood samples obtained from each individual, a decrease in global DNA methylation was observed in PD patients either exposed (49% of control, P < 0.001) or not exposed (47% of control, P < 0.001) to mining activity. Although there was no difference in levels of DNA methylation between PD patients from the two cities, there was a lower level of DNA methylation in control subjects from Santiago versus Antofagasta.
Assuntos
Metilação de DNA/genética , Exposição Ambiental , Epigênese Genética , Doença de Parkinson/epidemiologia , Análise de Variância , Chile/epidemiologia , Feminino , Humanos , Incidência , Masculino , Mineração , Doença de Parkinson/sangue , Sulfitos/metabolismoRESUMO
Mutations in the LRRK2 gene are the most common genetic cause of Parkinson's disease, with frequencies displaying a high degree of population-specificity. Although more than 100 coding substitutions have been identified, only seven have been proven to be highly penetrant pathogenic mutations. Studies however are lacking in non-white populations. Recently, Lrrk2 p.Q1111H (rs78365431) was identified in two affected Hispanic brothers and absent in 386 non-Hispanic white healthy controls. We therefore screened this variant in 1460 individuals (1150 PD patients and 310 healthy controls) from 4 Latin American countries (Peru, Chile, Uruguay and Argentina). In our case-control series from Peru and Chile we observed an increased frequency of Lrrk2 p.Q1111H in patients (7.9%) compared to controls (5.4%) although the difference did not reach significance (OR 1.38; p = 0.10). In addition, the frequency of Lrrk2 p.Q1111H varied greatly between populations and further screening in a set of pure Amerindian and pure Spanish controls suggested that this variant likely originated in an Amerindian population. Further studies in other Latin American populations are warranted to assess its role as a risk factor for Parkinson's disease. Screening in Parkinson's disease patients from under-represented populations will increase our understanding of the role of LRRK2 variants in disease risk worldwide.
Assuntos
Substituição de Aminoácidos/genética , Doença de Parkinson/etnologia , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Glutamina/genética , Histidina/genética , Humanos , Indígenas Sul-Americanos/etnologia , Indígenas Sul-Americanos/genética , América Latina/epidemiologia , América Latina/etnologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Adulto JovemRESUMO
Although it is generally accepted that free radicals are involved in the neurodegenerative process occurring in the dopaminergic neurons of the nigro-striatal system in Parkinson's disease, the exact mechanism of neurodegeneration in vivo is still unknown. We propose that the degeneration of dopaminergic nigrostriatal system in this condition may depend on: (a) existence of free dopamine which oxidizes to aminochrome as a consequence of: (i) overproduction of dopamine; (ii) inhibition and/or low expression of synaptic vesicle catecholamine transporter; (iii) inhibition or low expression of monoamine oxidases; (b) one-electron reduction of aminochrome to leukoaminochrome o-semiquinone radical, which induces neurotoxicity, due to inhibition of DT-diaphorase or the existence of a polymorphism with a point mutation (C --> T) in the cDNA 609 expressing an inactive DT-diaphorase. We suggest that DT-diaphorase plays a neuroprotective role in dopaminergic neurons, which is supported by the following observations: (i) Cu-toxicity is dependent on DT-diaphorase inhibition with dicoumarol in RCSN-3 cells derived from the rat substantia nigra; (ii) the cytotoxic effect of monoamine oxidase-A inhibitor amiflamine in RCSN-3 cells is increased by 2.4-fold (p < 0.001) in the presence of the inhibitor of DT-diaphorase, dicoumarol; (iii) concomitant intracerebral administration of manganese (Mn3+) together with the DT-diaphorase inhibitor dicoumarol into the left medial forebrain bundle produced a behavioral pattern characterized by contralateral rotational behavior when the rats were stimulated with apomorphine, in a manner similar to that observed in animals injected unilaterally with 6-hydroxydopamine; (iv) incubation of RCSN-3 cells with salsolinol in the presence of DT-diaphorase inhibitor significantly decreased cell survival by 2.5-fold (p < 0.001).
Assuntos
Dopamina/metabolismo , Indolquinonas , Indóis/metabolismo , NAD(P)H Desidrogenase (Quinona)/fisiologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/metabolismo , Animais , Dopamina/fisiologia , Humanos , Indóis/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Oxirredução/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/enzimologiaRESUMO
El síndrome a largo plazo por levodopa (L-Dopa) corresponde a las manifestaciones adversas provocadas por el fármaco, que aparecen generalmente después de un año o más de su empleo y que afectan aproximadamente al 50 por ciento de los casos. Los síntomas son muy variados y polimorfos, los más habituales son de tipo motor (diskinesias, distonías posturales y disminución de la respuesta motora), se agregan otros, como trastornos mentales, neurovegetativos y sensitivos. Para la profilaxis de este síndrome debe considerarse el retraso en la iniciación de la terapia, usándose como alternativa: selegilina, bromocriptina, anticolinérgicos (thihexifenidilo) o antidepresivos. En casos severos de enfermedad de Prkinson y que no pueda obviarse el uso de L-Dopa, ésta debe emplearse inicialmente en la dosis mínima efectiva, la que se aumenta en forma lenta y progresiva en varias semanas. Otra variables es el uso de formulaciones de liberación controlada (Prolopa HBS o Sinemet CR). También es recomendable la asociación de agonistas dopaminérgicos que tendrían un efecto protector en el síndrome a largo plazo de L-Dopa
Assuntos
Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Dopaminérgicos/administração & dosagem , Esquema de Medicação , Discinesia Induzida por Medicamentos/tratamento farmacológico , Manifestações Neurológicas , Transtornos Psicomotores/tratamento farmacológicoRESUMO
Las complicaciones motoras del tratamiento crónico con levodopa son: fluctuaciones motoras, diskinesias, disminución de la respuesta a levodopa. A éstas se agregan otras, que pudiendo presentarse en parkinsonianos no tratados, pueden ponerse más de manifiesto por la levodopa: distonía postural transitoria, episodios de congelamiento y calambres. Alcanzan a 50%de los pacientes al cabo de cuatro años, pudiendo en algunos casos ser invalidantes o intolerables. Están más propensos a ellas los parkinsonianos que comienzan la enfermedad antes o alrededor de los 40 años y los que inician el tratamiento en un grado avanzado de la enfermedad. Se describen estas complicaciones, su presentación porcentual y la probable fisiopatología. La mejor profilaxis es el tratamiento asociado desde el inicio con levodopa-ID y un agonista dopaminérgico, o el tratamiento de inicio sólo con este último hasta que se necesite de la asociación por disminución o pérdida de la eficacia. Esta última se explica por la interacción existente entre los receptores D1 y D2. Como tratamiento de las complicaciones ya producidas están los ajustes de dosis y mayor fraccionamiento horario del precursor dopaminérgico, la asociación de la levodopa-ID a agonistas dopaminérgicos orales, ahora con menor rendimiento que en la profilaxis, las nuevas formulaciones de levodopa de liberación sostenida, los agonistas dopaminérgicos parenterales e incluso, tal vez, el autotransplante de suprarrenal al caudado, las dos últimas medidas aún en etapa experimental
Assuntos
Discinesia Induzida por Medicamentos/diagnóstico , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológicoRESUMO
El trastorno postural constituye un síntoma relevante en la enfermedad de Parkinson especialmente en sus etapas avanzadas. La estabilidad postural requiere de la indemnidad de las aferencias vestibulares, propioceptivas y visuales integradas a un nivel superior. Un grupo de 17 pacientes parkinsonianos con trastorno postural (en estadios III y IV de la escala de Hoehn y Yahr) fueron sometidos a estimulación calórica bilateral simultánea a 18 y 48-C con el propósito de evaluar la conducta del reflejo vestibulo-ocular vertical como índice de función vestibular. El mismo procedimiento se realizó en un grupo control de 18 pacientes parkinsonianos sin trastorno postural (en estadios I y II de la escala de Hoehn y Yahr). No se encontraron diferencias significativas en los promedios de la velocidad angular de la componente lenta del nistagmus al comparar muchos grupos. Se observó una tendencia a presentar respuestas cuantitativamente mayores en el grupo sin trastorno postural. No se comprobó asociación entre trastorno postural y disfunción vestibular