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Doença de Parkinson: genética e farmacogenómica
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Abstract(s)
A Doença de Parkinson (DP) é uma doença crónica e neurodegenerativa. Nos dias de hoje as doenças neurológicas são a primeira causa de incapacidade a nível mundial e o seu estudo é de extrema importância pois a prevalência destas condições continua a aumentar.
A etiologia da DP encontra-se em grande parte por desvendar mas existem atualmente algumas teorias em relação à perda neuronal observada. Essas teorias envolvem inflamação, stress oxidativo, disfunção mitocondrial e processamento anormal de proteínas. Foi demostrado que fatores ambientais, comportamentais e genéticos podem encontrar-se relacionados com o aparecimento e desenvolvimento desta condição neurodegenerativa. A idade avançada e o sexo masculino são os maiores fatores de risco de DP.
A genética é um fator de risco substancial para o desenvolvimento de DP. A investigação da contribuição genética da patogénese de DP foi impulsionada pela identificação de mutações no gene codificante da α-sinucleína (SNCA) responsáveis pelo aparecimento da doença. Após essa descoberta surgiram outras investigações que identificaram vários genes adicionais, também eles implicados no aparecimento de DP. Foram também identificadas várias formas monogénicas da doença e numerosos fatores de risco genéticos. Mutações altamente penetrantes que resultam em formas monogénicas raras da doença são conhecidas em genes como SNCA, Parkina, DJ-1, PINK1, LRRK2 e VPS35. Verificou-se também que mutações de penetrância incompleta nos genes LRRK2 e GBA são fortes fatores de risco para a DP
Em termos da farmacogenómica de DP a informação disponível ainda é escassa, por isso, não permitindo, ainda, prever a variabilidade inter-individual da eficácia e toxicidade dos fármacos. No entanto, bastantes esforços estão a ser feitos para que num futuro próximo se consiga aplicar o conceito de terapêutica individualizada baseada na genética de cada individuo. Genes que codificam enzimas envolvidas no metabolismo da dopamina como o DRD2, COMT e DAT são alguns exemplos de genes que se encontram sob o olhar atento dos cientistas.
Parkinson’s disease (PD) is a chronic and neurodegenerative disease. Nowadays, neurological diseases are the first cause of disability worldwide and their study is extremely important because the prevalence of these conditions is increasing. The etiology of PD remains mostly unknown but there are some theories regarding the observed neuronal loss. These theories include inflammation, oxidative stress, mitochondrial dysfunction and abnormal protein processing. Studies have shown that environmental, behavioral and genetic factors may be related to the onset and development of this neurodegenerative condition. Advanced age and male gender are the major risk factors for PD development. An investigation identified the α-sinuclein (SNCA) gene as responsible for the appearance of the disease, leading to the promotion of additional research about the genetic contribution for PD pathogenesis. Other investigations emerged which identified several genes involved in the onset of PD. Several monogenic forms of the disease and genetic risk factors were also identified. Highly penetrating mutations in genes such as SNCA, Parkina, DJ-1, PINK1, LRRK2 and VPS35 result in rare monogenic forms of the disease. Incomplete penetrance mutations in LRKK2 and GBA genes have also been found to be strong risk factors for PD. In terms of PD pharmacogenomics the information available is still scarce and does not allow, presently, the prediction the inter-individual variability of efficacy and toxicity of drugs. However, a lot of efforts are being made to implement the concept of individualized therapy based on the genetics of each individual. Genes coding for enzymes involved in dopamine metabolism such as DRD2, COMT and DAT are some examples of genes that are under the watchful eye of scientists.
Parkinson’s disease (PD) is a chronic and neurodegenerative disease. Nowadays, neurological diseases are the first cause of disability worldwide and their study is extremely important because the prevalence of these conditions is increasing. The etiology of PD remains mostly unknown but there are some theories regarding the observed neuronal loss. These theories include inflammation, oxidative stress, mitochondrial dysfunction and abnormal protein processing. Studies have shown that environmental, behavioral and genetic factors may be related to the onset and development of this neurodegenerative condition. Advanced age and male gender are the major risk factors for PD development. An investigation identified the α-sinuclein (SNCA) gene as responsible for the appearance of the disease, leading to the promotion of additional research about the genetic contribution for PD pathogenesis. Other investigations emerged which identified several genes involved in the onset of PD. Several monogenic forms of the disease and genetic risk factors were also identified. Highly penetrating mutations in genes such as SNCA, Parkina, DJ-1, PINK1, LRRK2 and VPS35 result in rare monogenic forms of the disease. Incomplete penetrance mutations in LRKK2 and GBA genes have also been found to be strong risk factors for PD. In terms of PD pharmacogenomics the information available is still scarce and does not allow, presently, the prediction the inter-individual variability of efficacy and toxicity of drugs. However, a lot of efforts are being made to implement the concept of individualized therapy based on the genetics of each individual. Genes coding for enzymes involved in dopamine metabolism such as DRD2, COMT and DAT are some examples of genes that are under the watchful eye of scientists.
Description
Keywords
Doença de Parkinson Genética Farmacogenómica Fatores de risco Patogénese