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Estudo do papel de uma proteína ligante de RNA num modelo animal das doenças de poliglutaminas
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Abstract(s)
As doenças de poliglutaminas são um grupo de nove doenças neurodegenerativas raras causadas por uma expansão anormal do trinucleótido CAG no gene causador, que codifica um segmento de poliglutaminas expandido na respetiva proteína. Estas proteínas tendem a agregar, formando agregados de proteína insolúveis, que é uma característica neuropatológica das doenças de poliglutaminas. Os mecanismos moleculares da patogénese de doenças de poliglutaminas ainda não são completamente compreendidos. Além disso, atualmente não estão disponíveis opções terapêuticas para estas doenças raras, que parem ou atrasem a sua progressão e que infelizmente culmina com a morte dos doentes.
A regulação da expressão genética é um processo crucial através do qual as células eucarióticas respondem e adaptam-se a diferentes estímulos. Quando os mRNAs sofrem transcrição, eles são sujeitos a alterações que controlam a tradução e estabilidade do mRNA, eventos que são regulados por proteínas ligantes de RNA (RBPs). Os eventos de processamento de RNA desempenham um papel fundamental na regulação do desenvolvimento cerebral e funcionamento normal, o que significa que defeitos no metabolismo do RNA podem levar a comprometimentos neuronais e sinápticos, que podem acabar por desencadear patologias. Refletindo esta importância, mais de 50% dos RBPs conhecidos são expressos no cérebro, onde estão envolvidos em diferentes processos como splicing alternativo, transporte, localização, estabilidade e tradução de RNAs.
O nosso objetivo neste projeto foi estudar o impacto da sobreexpressão de G3BP1 num modelo transgénico de doenças de poliglutaminas. Foi possível verificar que o cruzamento de murganhos heterozigóticos SCA3/MDJ com animais wild-type gera murganhos transgénicos. Estudos in vivo revelaram que a sobrexpressão de G3BP1 conduz à melhoria do fenótipo motor e da neuropatologia de murganhos com SCA3/MJD. Em conclusão, estes resultados sugerem que a sobreexpressão de G3BP1 apresenta um efeito neuroprotetor. No entanto, são necessários mais estudos para compreender o mecanismo molecular responsável por este efeito.
Polyglutamine (PolyQ) diseases are a group of nine rare neurodegenerative disorders caused by an abnormal expansion of the trinucleotide CAG in the causative gene, which encodes a PolyQ tract in their respective protein. These proteins carrying an abnormally expanded PolyQ tract tend to aggregate, forming insoluble protein aggregates, which are a key feature of PolyQ diseases. The molecular mechanisms underlying PolyQ diseases pathogenesis are not yet fully understood. Moreover, currently there are no therapeutic options available for these rare diseases stopping or delaying the disease progression, which culminates with patient death. The regulation of gene expression is a crucial process whereby eukaryotic cells respond and adapt to different stimuli. Once mRNAs undergo transcription, they are subjected to posttranscriptional changes controlling mRNA translation and stability, events that are regulated by the RNA-binding proteins (RBPs). The RNA processing events play a major role in the regulation of brain development and normal functioning, meaning that defects in RNA metabolism could lead to neuronal and synaptic impairments, which ultimately might lead to disease. Reflecting this importance, more than 50% of known RBPs are expressed in the brain, where they are involved in different processes such as alternative splicing, transport, localization, and stability and translation of RNAs. Our goal in this project was to study the impact of the overexpression of G3BP1 in a transgenic mouse model of PolyQ diseases. It was possible to verify that the crossing of heterozygotic SCA3/MJD mice with wild-type animals generates transgenic mice. In vivo studies revealed that the G3BP1 overexpression can ameliorate the motor phenotype and neuropathology in SCA3/MJD mice. In conclusion, these results suggest that G3BP1 overexpression displays a neuroprotective effect. Although, further studies are required to fully understand the molecular mechanism of action responsible for this effect.
Polyglutamine (PolyQ) diseases are a group of nine rare neurodegenerative disorders caused by an abnormal expansion of the trinucleotide CAG in the causative gene, which encodes a PolyQ tract in their respective protein. These proteins carrying an abnormally expanded PolyQ tract tend to aggregate, forming insoluble protein aggregates, which are a key feature of PolyQ diseases. The molecular mechanisms underlying PolyQ diseases pathogenesis are not yet fully understood. Moreover, currently there are no therapeutic options available for these rare diseases stopping or delaying the disease progression, which culminates with patient death. The regulation of gene expression is a crucial process whereby eukaryotic cells respond and adapt to different stimuli. Once mRNAs undergo transcription, they are subjected to posttranscriptional changes controlling mRNA translation and stability, events that are regulated by the RNA-binding proteins (RBPs). The RNA processing events play a major role in the regulation of brain development and normal functioning, meaning that defects in RNA metabolism could lead to neuronal and synaptic impairments, which ultimately might lead to disease. Reflecting this importance, more than 50% of known RBPs are expressed in the brain, where they are involved in different processes such as alternative splicing, transport, localization, and stability and translation of RNAs. Our goal in this project was to study the impact of the overexpression of G3BP1 in a transgenic mouse model of PolyQ diseases. It was possible to verify that the crossing of heterozygotic SCA3/MJD mice with wild-type animals generates transgenic mice. In vivo studies revealed that the G3BP1 overexpression can ameliorate the motor phenotype and neuropathology in SCA3/MJD mice. In conclusion, these results suggest that G3BP1 overexpression displays a neuroprotective effect. Although, further studies are required to fully understand the molecular mechanism of action responsible for this effect.
Description
Keywords
Proteínas ligantes de rna Grânulos de stress Agregação Neurodegeneração Doenças de poliglutaminas