A força motriz por trás das fa¡bricas de proteanas celulares pode ter implicações para doenças neurodegenerativas
Os pesquisadores identificaram a força motriz por trás de um processo celular ligado a doenças neurodegenerativas, como Parkinson e doença do neura´nio motor.
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Induzir o movimento antera³grado do lisossoma (verde) com luz leva a uma extensão rápida e significativa da rede ER (magenta). Crédito: Clemens Kaminski
Ainda hámuito a aprender sobre esse sistema, que éextremamente importante para a ciência biomédica fundamental
Clemens Kaminski
Em um estudo publicado hoje na Science Advances , pesquisadores da Universidade de Cambridge mostram que minaºsculos componentes dentro da canãlula são os motores biola³gicos por trás da produção eficaz de proteanas.
O retaculo endoplasma¡tico (RE) éa fa¡brica de proteanas da canãlula, produzindo e modificando as proteanas necessa¡rias para garantir a função celular sauda¡vel. a‰ a maior organela da canãlula e existe em uma estrutura semelhante a uma teia de tubos e folhas. O ER se move rapidamente e muda constantemente de forma, estendendo-se pela canãlula para onde for necessa¡rio em um determinado momento.
Usando técnicas de microscopia de super-resolução, pesquisadores do Departamento de Engenharia Química e Biotecnologia (CEB) de Cambridge descobriram a força motriz por trás desses movimentos - um avanço que poderia ter impacto significativo no estudo de doenças neurodegenerativas.
“a‰ sabido que o retaculo endoplasma¡tico tem uma estrutura muito dina¢mica - esticando e estendendo constantemente sua forma dentro da canãlulaâ€, disse o Dr. Meng Lu, pesquisador associado do Grupo de Ana¡lise de Laser, liderado pelo Professor Clemens Kaminski.
“O ER precisa ser capaz de chegar a todos os lugares com eficiência e rapidez para realizar funções de limpeza essenciais dentro da canãlula, quando e onde houver necessidade. A diminuição desta capacidade estãoassociada a doenças como Parkinson, Alzheimer, Huntington e ALS. Atéagora, houve uma compreensão limitada de como o ER atinge essasmudanças rápidas e fascinantes na forma e como ele responde aos estamulos celulares. â€
Lu e seus colegas descobriram que outro componente celular detanãm a chave - pequenas estruturas, que se parecem com pequenas gotaculas contidas nas membranas, chamadas lisossomas.
Os lisossomos podem ser considerados centros de reciclagem das células: eles capturam proteanas danificadas, quebrando-as em seus blocos de construção originais para que possam ser reutilizadas na produção de novas proteanas. Os lisossomos também atuam como centros de detecção - captando sinais ambientais e os comunicando a outras partes da canãlula, que se adaptam de acordo.
Pode haver cerca de 1.000 lisossomos circulando pela canãlula a qualquer momento e, com eles, o ER parece mudar sua forma e localização, de uma forma aparentemente orquestrada.
O que surpreendeu os cientistas de Cambridge foi a descoberta de uma ligação causal entre o movimento dos minaºsculos lisossomos dentro da canãlula e o processo de remodelagem da grande rede ER.
“Poderaamos mostrar que éo movimento dos pra³prios lisossomos que força o ER a se remodelar em resposta a estamulos celularesâ€, disse Lu. “Quando a canãlula sente que hánecessidade de lisossomos e ER para viajar para os cantos distais da canãlula, os lisossomas puxam a teia ER junto com eles, como minaºsculas locomotivas.â€
Do ponto de vista biola³gico, isso faz sentido: os lisossomas atuam como um sensor dentro da canãlula, e o ER como uma unidade de resposta; coordenar sua função sancrona éfundamental para a saúde celular.
Para descobrir esse vanculo surpreendente entre duas organelas muito diferentes, a equipe de pesquisa de Kaminski fez uso de novas tecnologias de imagem e algoritmos de aprendizado de ma¡quina, que deram a eles insights sem precedentes sobre o funcionamento interno da canãlula.Â
“a‰ fascinante que agora possamos olhar dentro das células vivas e ver a velocidade e a dina¢mica maravilhosas da maquinaria celular com tantos detalhes e em tempo realâ€, disse Kaminski. “Apenas alguns anos atrás, assistir organelas fazendo seus nega³cios dentro da canãlula seria impensa¡vel.â€
Os pesquisadores usaram padraµes de iluminação projetados em células vivas em alta velocidade e algoritmos de computador avana§ados para recuperar informações em uma escala mais de cem vezes menor do que a largura de um cabelo humano. Capturar essas informações em taxas de vadeo são recentemente se tornou possível.
Os pesquisadores também usaram algoritmos de aprendizado de ma¡quina para extrair a estrutura e o movimento das redes ER e lisossomos de forma automatizada de milhares de conjuntos de dados.
A equipe estendeu sua pesquisa para examinar neura´nios ou células nervosas - células especializadas com longas protubera¢ncias chamadas axa´nios ao longo das quais os sinais são transmitidos. Axa´nios são estruturas tubulares extremamente finas e não se sabia como o movimento da grande rede ER éorquestrado dentro dessas estruturas.
O estudo mostra como os lisossomos viajam facilmente ao longo dos axa´nios e arrastam o ER atrás deles. Os pesquisadores também mostram como impedir esse processo éprejudicial ao desenvolvimento de neura´nios em crescimento.
Frequentemente, os pesquisadores viram eventos onde os lisossomos agiam como motores de reparo para pea§as desconectadas ou quebradas da estrutura ER, fundindo-as e fundindo-as em uma rede intacta novamente. O trabalho anã, portanto, relevante para a compreensão dos distúrbios do sistema nervoso e seu reparo.
A equipe também estudou o significado biola³gico desse movimento acoplado, fornecendo um estamulo - neste caso nutrientes - para os lisossomos sentirem. Os lisossomos foram vistos movendo-se em direção a este sinal, arrastando a rede ER para trás de modo que a canãlula possa eliciar uma resposta adequada.
“Atéagora, pouco se sabia sobre a regulação da estrutura do ER em resposta a sinais metaba³licosâ€, disse Lu. “Nossa pesquisa fornece uma ligação entre os lisossomos como unidades de sensores que orientam ativamente a resposta ER local.â€
A equipe espera que seus insights sejam inestima¡veis ​​para aqueles que estudam as ligações entre a doença e a resposta celular, e que seus pra³ximos passos sejam focados no estudo da função e disfunção do ER em doenças como Parkinson e Alzheimer.
Os distúrbios neurodegenerativos estãoassociados a agregação de proteanas danificadas e mal dobradas, portanto, compreender os mecanismos subjacentes da função do ER éfundamental para pesquisar seu tratamento e prevenção. Â
“As descobertas do ER e dos lisossomos receberam o Praªmio Nobel hámuitos anos - eles são organelas essenciais para a função celular sauda¡velâ€, disse Kaminski. “a‰ fascinante pensar que ainda hámuito a aprender sobre esse sistema, que éextremamente importante para a ciência biomédica fundamental que busca encontrar a causa e a cura para essas doenças devastadoras.â€