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The impact of aging in mutant ataxin-2 induced neurodegeneration
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Abstract(s)
Com o aumento da esperança de vida, cada vez mais aparecem doenças que previamente se desconheciam. Portanto, estas doenças não têm cura definitiva, existindo apenas terapêutica para alívio dos sintomas. As doenças neurodegenerativas inserem-se neste grupo de doenças sem cura. À medida que a idade aumenta, o cérebro é afetado pela diminuição e desregulação de certos mecanismos intra e intercelulares. É o caso da autofagia, cuja função de degradação e reciclagem de proteínas e organelos diminui durante o desenvolvimento. Nisto resulta, a acumulação de proteínas de conformação anormal e na formação de agregados proteicos que se tornam evidentes nos neurónios. As doenças de poliglutaminas são um grupo de nove doenças neurodegenerativas, que engloba a Ataxia Espinocerebelosa do tipo 2 (SCA2). A SCA2 é provocada pela expansão anormal do trato CAG que codifica para uma expansão anormal de glutaminas na proteína responsável pela patologia, ATAXINA-2. Dois achados comuns das doenças de poliglutaminas são a presença de agregados neuronais da proteína mutante nas regiões afetadas do cérebro e a desregulação do mecanismos de degradação proteica, como a autofagia. Este projeto teve como objetivo avaliar o efeito da neurodegeneração causada pela ATAXINA-2 mutante nos murganhos jovens e idosos. O aumento da idade contribuiu para um aumento na formação de agregados de ATAXINA-2 mutante e também para a perda neuronal. Os danos nas células provocados pela proteína mutada conduzem à ativação da resposta inflamatória através do recrutamento de astrócitos e ativação da microglia, que se torna mais acentuado numa idade mais avançada. Além disso, a ATAXINA-2 mutada provoca uma redução da ativação da via apoptótica e da quantidade de histonas e, possivelmente, o recrutamento do PABP para os agregados proteicos. Contudo, não foram observadas alterações nos sistemas autofágicos, mitocondriais, sinápticos e na sensitividade da regulação de nutrientes.
With the increase in life expectancy, diseases that were previously unknown have increasingly appear. Therefore, these diseases have no definitive cure, therefore only exists therapy for symptoms relief. Neurodegenerative diseases are part of this group of diseases with no cure. As age increases, the brain is affected by the decrease and dysregulation of certain intra and intercellular mechanisms. This is the case of autophagy; whose function of degradation and recycling proteins and organelles decreases during aging. This results in the accumulation of abnormally shaped proteins and the formation of protein aggregates that become evident in neurons. Polyglutamine diseases are a group of nine neurodegenerative diseases, including type 2 spinocerebellar ataxia (SCA2). SCA2 is caused by the abnormal expansion of the CAG tract that encodes for an abnormal expansion of glutamines in the protein responsible for the pathology, ATAXIN-2. Two common hallmarks of polyglutamine diseases are the presence of neuronal aggregates of the mutant protein in the affected regions of the brain and the dysregulation of protein degradation mechanisms, such as autophagy. This project aimed to evaluate the effect of neurodegeneration caused by the mutant ATAXIN-2 on young and old mice. The increase in age contributed to an increase of the formation of mutant ATAXIN-2 aggregates and also to neuronal loss. Cell damage caused by the mutated protein leads to the activation of the inflammatory response through the recruitment of astrocytes and activation of the microglia, which becomes more pronounced at an older age. In addition, the mutated ATAXIN-2 causes a reduction in the activation of the apoptotic pathway and the number of histones and possibly the recruitment of PABP to protein aggregates. However, no changes were observed in the autophagic, mitochondrial, synaptic systems and in the sensitivity of nutrient regulation.
With the increase in life expectancy, diseases that were previously unknown have increasingly appear. Therefore, these diseases have no definitive cure, therefore only exists therapy for symptoms relief. Neurodegenerative diseases are part of this group of diseases with no cure. As age increases, the brain is affected by the decrease and dysregulation of certain intra and intercellular mechanisms. This is the case of autophagy; whose function of degradation and recycling proteins and organelles decreases during aging. This results in the accumulation of abnormally shaped proteins and the formation of protein aggregates that become evident in neurons. Polyglutamine diseases are a group of nine neurodegenerative diseases, including type 2 spinocerebellar ataxia (SCA2). SCA2 is caused by the abnormal expansion of the CAG tract that encodes for an abnormal expansion of glutamines in the protein responsible for the pathology, ATAXIN-2. Two common hallmarks of polyglutamine diseases are the presence of neuronal aggregates of the mutant protein in the affected regions of the brain and the dysregulation of protein degradation mechanisms, such as autophagy. This project aimed to evaluate the effect of neurodegeneration caused by the mutant ATAXIN-2 on young and old mice. The increase in age contributed to an increase of the formation of mutant ATAXIN-2 aggregates and also to neuronal loss. Cell damage caused by the mutated protein leads to the activation of the inflammatory response through the recruitment of astrocytes and activation of the microglia, which becomes more pronounced at an older age. In addition, the mutated ATAXIN-2 causes a reduction in the activation of the apoptotic pathway and the number of histones and possibly the recruitment of PABP to protein aggregates. However, no changes were observed in the autophagic, mitochondrial, synaptic systems and in the sensitivity of nutrient regulation.
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Keywords
Eestriado Envelhecimento Ataxina-2 Autofagia Agregados Neurodegeneração