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Abstract(s)
A doença de Machado-Joseph (DMJ) ou ataxia espinocerebelosa do tipo 3 (SCA3),
conhecida por ser a mais comum das ataxias hereditárias dominantes em todo o mundo, é uma
doença neurodegenerativa autossómica dominante que leva a uma grande incapacidade
motora, embora sem alterar o intelecto, culminando com a morte do doente. Atualmente não
existe nenhum tratamento eficaz para esta doença.
A DMJ é resultado de uma alteração genética causada pela expansão de uma sequência
poliglutamínica (poliQ), na região C-terminal do gene que codifica a proteína ataxina-3
(ATXN3). Os mecanismos celulares das doenças de poliglutaminas que provocam toxicidade,
bem como a função da ATXN3, não são ainda totalmente conhecidos.
Neste trabalho, usamos, pela sua simplicidade e potencial genético, um pequeno
animal invertebrado, o nemátode C. elegans, com o objetivo de identificar fármacos eficazes
para o combate contra a patogénese da DMJ, analisando simultaneamente o seu efeito na
agregação da ATXN3 mutante nas células neuronais in vivo e o seu impacto no
comportamento motor dos animais. Este pequeno invertebrado proporciona grandes vantagens
no estudo dos efeitos tóxicos de proteínas poliQ nos neurónios, uma vez que a transparência
das suas 959 células (das quais 302 são neurónios) facilita a deteção de proteínas
fluorescentes in vivo. Para além disso, esta espécie tem um ciclo de vida curto, é económica e
de fácil manutenção.
Neste trabalho testámos no nosso modelo transgénico da DMJ com 130Qs em
C.elegans dois compostos potencialmente moduladores da agregação da ATXN3 mutante e da
resultante disfunção neurológica, atuando pela via da autofagia. De modo a validar a possível
importância terapêutica da ativação da autofagia os compostos candidatos escolhidos foram o
Litío e o análogo da Rapamicina CCI-779, testados independentemente e em combinação. A
neuroproteção conferida pelo Litío e pelo CCI-779 independentemente sugere que o uso
destes fármacos possa ser considerado uma boa estratégia como terapia para a DMJ, a testar
em organismos evolutivamente mais próximos do humano. A manipulação da autofagia,
segundo vários autores, parece ser benéfica e pode ser a chave para o desenvolvimento de
novos tratamentos para várias doenças relacionadas com a agregação proteica e o
envelhecimento.
Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), known to be the most dominan common of the hereditary ataxias worldwide, is an autosomal dominant neurodegenerative disease that leads to a marked motor disability, although never changing the intellect, culminating in the death of the patient. Currently there is no effective treatment for this disease. MJD is a result of a genetic change caused by the expansion of polyglutamine (polyQ) sequence in the C-terminal region of the gene that encodes the protein ataxin-3 (ATXN3). The cellular mechanisms of polyglutamine disease that cause toxicity and also the function of ATXN3 are not yet fully understood. In this paper, we use, for its simplicity and genetic potential, a small invertebrate animal, the nematode C. elegans, with the goal of identifying effective drugs to combat the pathogenesis of MJD, simultaneously analyzing their effect on the aggregation of mutant ATXN3 in neuronal cells in vivo and their impact on, the locomotion behavior of these animals. This small invertebrate provides great advantages in studying the toxicity of polyQ proteins in neurons, because of its 959 transparent cells (of which 302 are neurons) which make the proccess of detection of fluorescent proteins in vivo easy. Furthermore, this species has a short life cycle, it is economic and easy to maintain. In this work we have tested in our transgenic model of MJD 130Qs in C.elegans two compounds with the potential to modulate the aggregation of mutant ATXN3 and the results neurological dysfunction, through the autophagy pathway. In order to validate the possible therapeutic importance of activation of autophagy the candidate compounds chosen were lithium and the analog of Rapamycin CCI-779 tested independently and also in combination. The neuroprotection conferred by lithium and CCI-779 independently suggests that the use of these drugs may be considered as a good strategy for therapy in MJD and worldwide to test in organisms evolutionarily closer to humans. Manipulation of autophagy, according to several authors, seems to be benefic and may be key to the development of new treatments for various protein aggregation and aging-related diseases.
Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), known to be the most dominan common of the hereditary ataxias worldwide, is an autosomal dominant neurodegenerative disease that leads to a marked motor disability, although never changing the intellect, culminating in the death of the patient. Currently there is no effective treatment for this disease. MJD is a result of a genetic change caused by the expansion of polyglutamine (polyQ) sequence in the C-terminal region of the gene that encodes the protein ataxin-3 (ATXN3). The cellular mechanisms of polyglutamine disease that cause toxicity and also the function of ATXN3 are not yet fully understood. In this paper, we use, for its simplicity and genetic potential, a small invertebrate animal, the nematode C. elegans, with the goal of identifying effective drugs to combat the pathogenesis of MJD, simultaneously analyzing their effect on the aggregation of mutant ATXN3 in neuronal cells in vivo and their impact on, the locomotion behavior of these animals. This small invertebrate provides great advantages in studying the toxicity of polyQ proteins in neurons, because of its 959 transparent cells (of which 302 are neurons) which make the proccess of detection of fluorescent proteins in vivo easy. Furthermore, this species has a short life cycle, it is economic and easy to maintain. In this work we have tested in our transgenic model of MJD 130Qs in C.elegans two compounds with the potential to modulate the aggregation of mutant ATXN3 and the results neurological dysfunction, through the autophagy pathway. In order to validate the possible therapeutic importance of activation of autophagy the candidate compounds chosen were lithium and the analog of Rapamycin CCI-779 tested independently and also in combination. The neuroprotection conferred by lithium and CCI-779 independently suggests that the use of these drugs may be considered as a good strategy for therapy in MJD and worldwide to test in organisms evolutionarily closer to humans. Manipulation of autophagy, according to several authors, seems to be benefic and may be key to the development of new treatments for various protein aggregation and aging-related diseases.
Description
Keywords
Ataxia Ataxia espinocerebelosa Doença de Machado-Joseph Ataxina-3 ATXN3 Spinocerebellar ataxia Machado-Joseph disease Ataxin-3 ATXN3
Citation
Publisher
Instituto Politécnico do Porto. Escola Superior de Tecnologia da Saúde do Porto