4 research outputs found
Estudo dos polimorfismos genéticos de enzimas antioxidantes nas Doenças de Alzheimer e Parkinson
Doenças neurodegenerativas Ă© um termo genĂ©rico utilizado para um espetro de condiçÔes que afetam principalmente as cĂ©lulas neuronais. De entre as cĂ©lulas neuronais os neurĂłnios tĂȘm sido os mais estudados em relação a este tipo de patologia. Os neurĂłnios sĂŁo cĂ©lulas que constituem o sistema nervoso, e sĂŁo cĂ©lulas pĂłs-mitĂłticas pelo que quando sĂŁo danificadas ou morrem nĂŁo hĂĄ hipĂłtese de substituição (Emerit et al. 2004). As doenças neurodegenerativas sĂŁo doenças incurĂĄveis e debilitantes que resultam na progressiva degeneração e/ou morte das cĂ©lulas nervosas. Este facto leva a que o doente apresente alteraçÔes nos movimentos (ataxia) ou que desenvolva demĂȘncia (Guyton & Hall 2006). No presente trabalho as doenças neurodegenerativas abordadas sĂŁo a Doença de Alzheimer e a Doença de Parkinson. Estas patologias tĂȘm em comum o facto de serem frequentemente associadas ao processo de stress oxidativo, razĂŁo pela qual Ă© importante avaliar a capacidade de defesa antioxidante nestas patologias, como por exemplo os parĂąmetros genĂ©ticos das enzimas antioxidantes como a GST. Sendo assim este trabalho tem como objetivo estudar a relação dos polimorfismos GSTM1 e GSTT1 com as Doenças de Alzheimer e Parkinson.
A população em estudo Ă© constituĂda por 58 indivĂduos de nacionalidade Portuguesa, das quais 35 foram diagnosticados com Doença de Alzheimer e 23 com Doença de Parkinson, e a população controlo Ă© constituĂda por 154 pessoas. As amostras de sangue foram colhidas em papel de filtro, de onde se extraiu o DNA atravĂ©s do mĂ©todo de ChelexÂź 100, posteriormente se realizou a amplificação por PCR dos genes de interesse e identificou-se o genĂłtipo atravĂ©s da eletroforese em gel de agarose.
Os resultados mostraram que as GSTs tĂȘm influĂȘncia em ambas as patologias. Na Doença de Alzheimer Ă© de salientar que principalmente o genĂłtipo GSTM1 âausenteâ Ă© um fator de risco para o desenvolvimento da doença. Na Doença do Parkinson os genĂłtipos GSTM1 e GSTT1 âausentesâ parecem ser um fator de risco para os indivĂduos do sexo masculino, jĂĄ nos indivĂduos do sexo feminino o que se verifica Ă© a prevalĂȘncia do genĂłtipo GSTT1 âpresenteâ.Neurodegenerative diseases, it is a generic term for a spectrum of conditions that primarily affect neuronal cells. Among the neuronal cells, neurons have been most studied and associated with this type of pathology. Neurons are cells that constitute the nervous system, as they are post-mitotic cells, when they are damaged or die, they canât be replaced (Emerit et al. 2004). Neurodegenerative diseases are incurable and debilitating diseases that result in the progressive degeneration and/or death of the neuronal cells. This leads to the patient presenting changes in the movements (ataxia) or to develop dementia (Guyton and Hall 2006). In the present work, the neurodegenerative diseases studied are Alzheimer's Disease and Parkinson's Disease. These disorders have in common the fact that they are often associated with oxidative stress, which is why it is important to evaluate the ability of antioxidant defense in these pathologies, such as genetic parameters of antioxidant enzymes such as GST. This work aims to study the relationship between GSTM1 and GSTT1 polymorphisms with Alzheimer's Disease and Parkinsonâs Disease.
The study population consists of 58 individuals of Portuguese nationality, of which 35 were diagnosed with Alzheimer's disease and 23 with Parkinson's disease, and the control population is formed by 154 people. Blood samples were collected on filter paper, from which DNA was extracted using the ChelexÂź 100 method, then the amplification of the genes of interest was carried out by PCR and the genotype was identified by agarose gel electrophoresis.
The results showed that GSTs play an important role in both diseases. In Alzheimer's disease, it is particularly noteworthy that GSTM1 null genotype" is a risk factor for the disease development. In Parkinson's disease the GSTM1 and GSTT1 null genotypes appear to be a risk factor for men, while in the women it is noticed the prevalence of GSTT1 present genotype
Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction
Tauopathies such as Alzheimer's disease are characterized by aggregation and increased phosphorylation of the microtubule-associated protein tau. Tau's pathological changes are closely linked to neurodegeneration, making tau a prime candidate for intervention. We developed an approach to monitor pathological changes of aggregation-prone human tau in living neurons. We identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that interact with tau and modulate tau kinases. We found that PHOX15 inhibits tau aggregation, restores tau's physiological microtubule interaction, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and suggest that PHOX15 binding reduces the protofilament's ability to adopt a PHF-like conformation by modifying a key glycine triad. Our data demonstrate that live-cell imaging of a tauopathy model enables screening of compounds that modulate tau-microtubule interaction and allows identification of a promising polypharmacological drug candidate that simultaneously inhibits tau aggregation and reduces tau phosphorylation.</p