Cerca de uma em cada cinco pessoas carrega uma versão de um gene que - embora em grande parte desconhecido - parece conferir proteção contra a doença de Alzheimer e a doença de Parkinson, descobriram os investigadores de Stanford e seus colegas.
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)
A depuração imunológica das sequências acetiladas de PHF6 tau pode reduzir a neurodegeneração na DA e na DP. Sementes patológicas de tau, fragmentos solúveis de tau ou tau mal dobrada presentes no espaço extracelular são captadas e fagocitadas pela microglia ativada, onde são processadas. Além da autofagia, os fragmentos de peptídeo tau resultantes, notadamente a lisina acetilada (K-ac) 311 PHF6, estão ligados a HLA-DRB1*04:01 ou HLA-DRB1*04:04 e os complexos HLA-peptídeo resultantes apresentados pelas células microgliais ( ou outras células apresentadoras de antígeno) para células T auxiliares CD4+. As células T CD4 + desencadeiam respostas imunes benéficas a jusante, talvez envolvendo CD8 +Células T e B produtoras de anticorpos. Estas respostas limitam a propagação da tau mal dobrada e reduzem a neuropatologia, explicando também a redução da tau no LCR em indivíduos HLA-DRB1*04. Crédito: Anais da Academia Nacional de Ciências (2023). DOI: 10.1073/pnas.2302720120
Cerca de uma em cada cinco pessoas carrega uma versão de um gene que - embora em grande parte desconhecido - parece conferir proteção contra a doença de Alzheimer e a doença de Parkinson, descobriram os investigadores da Stanford Medicine e seus colegas. Estas pessoas sortudas poderão algum dia beneficiar ainda mais de uma vacina que possa retardar ou travar a progressão destas duas doenças neurodegenerativas mais comuns.
Uma análise de dados médicos e genéticos de centenas de milhares de pessoas de diversas ascendências de vários continentes revelou que transportar esta versão do gene, ou alelo, reduziu as probabilidades de as pessoas contraírem Parkinson ou Alzheimer em mais de 10%, em média.
As evidências sugerem que uma proteína chamada tau, que é notória por se agregar nos cérebros dos pacientes com Alzheimer, também pode estar envolvida, de alguma forma misteriosa, no desenvolvimento da doença de Parkinson.
As descobertas e implicações são descritas em um artigo publicado on-line em 29 de agosto no Proceedings of the National Academy of Sciences . Emmanuel Mignot, MD, Ph.D., professor Craig Reynolds em Medicina do Sono e professor de psiquiatria e ciências comportamentais , compartilha a autoria sênior com Michael Greicius, MD, professor Iqbal Farrukh e Asad Jamal e professor de neurologia e ciências neurológicas e Jean-Charles Lambert, Ph.D., diretor de pesquisa do Inserm na Universidade de Lille, na França. Os principais autores são Yann Le Guen, Ph.D., diretor assistente de biologia computacional na unidade de ciências quantitativas da Stanford Medicine; Guo Luo, Ph.D., instrutor de medicina do sono; ex-bolsista de pós-doutorado Aditya Ambati, Ph.D.; e Vincent Damotte, Ph.D., bioinformático associado ao grupo de Lambert.
O alelo protetor identificado no estudo é denominado DR4.
“Num estudo anterior descobrimos que carregar o alelo DR4 parecia proteger contra a doença de Parkinson”, disse Mignot. “Agora, descobrimos um impacto semelhante do DR4 na doença de Alzheimer”.
A equipe da Stanford Medicine combinou dezenas de bancos de dados médicos e genéticos coletados em vários países – na Europa, no Leste Asiático, no Oriente Médio e nas Américas do Sul e do Norte. Ao todo, os bancos de dados incluíam mais de 100 mil pessoas com doença de Alzheimer e mais de 40 mil com doença de Parkinson. Os cientistas compararam a incidência e a idade de início da doença de Alzheimer e Parkinson entre pessoas com DR4 e aquelas sem doença e encontraram uma redução de risco de cerca de 10% naqueles portadores de DR4.
“O fato de esse fator protetor para o Parkinson acabar tendo o mesmo efeito protetor em relação ao Alzheimer me deixou chocado”, disse Mignot. "Na noite seguinte à descoberta disso, não consegui dormir."
Os investigadores também analisaram dados de cérebros autopsiados de mais de 7.000 pacientes com Alzheimer e descobriram que os portadores de DR4 tinham menos emaranhados neurofibrilares – agregados longos e filamentosos, compostos em grande parte por tau, que caracterizam a doença de Alzheimer – bem como um início mais tardio dos sintomas, do que suas contrapartes não-DR4. Foi demonstrado que a presença de emaranhados neurofibrilares está fortemente correlacionada com a gravidade da doença.
Portar DR4 também se correlacionou com um início mais tardio de sintomas em pacientes com Parkinson, embora os emaranhados neurofibrilares não sejam normalmente observados nessa doença.
Este estudo sugere que a tau, um agente essencial na doença de Alzheimer, pode vir a desempenhar também algum tipo de papel na doença de Parkinson, disse Mignot, embora não esteja claro qual pode ser esse papel.
A superfície de uma célula é sua janela de exibição
DR4 é um entre os copiosos alelos de um gene chamado DRB1, que por si só é um entre muitos em um grande complexo de genes – chamado complexo de antígeno linfocitário humano, ou HLA – que é crucial para tornar o conteúdo interno das células visível ao sistema imunológico.
A membrana externa de uma célula mantém o interior da célula para dentro e o exterior para fora. Mas não é só isso. Também serve como janela de exibição, expondo fragmentos das proteínas contidas nele ao sistema imunológico.
A exposição rotineira desses fragmentos, ou peptídeos – fragmentos independentes de proteínas picadas – na superfície da célula (sua membrana externa) permite que células imunes itinerantes os examinem. Ao inspecionar os peptídeos da superfície celular, essas células imunológicas patrulhadoras podem ver se há algo engraçado acontecendo dentro dela – ou seja, se alguma proteína estranha ou alterada pode residir na célula, implicando uma infecção ou estado canceroso, respectivamente.
Facilitando essa vitrine estão proteínas especializadas que podem agarrar e envolver todos esses peptídeos e exibi-los nas superfícies celulares de uma forma ideal para o reconhecimento imunológico. Estas proteínas especializadas são produtos dos genes HLA.
Cada um dos numerosos genes HLA vem em uma grande variedade de alelos. Cada um de nós herda uma coleção diferente desses alelos. Como os produtos proteicos de diferentes alelos HLA se ligam a diferentes conjuntos de peptídeos, a variedade de peptídeos que as células de uma pessoa exibem para vigilância imunológica varia de uma pessoa para outra.
Quando o sistema imunológico detecta um peptídeo na superfície que pensa nunca ter visto antes, ele pode montar um ataque poderoso a qualquer célula que exiba esse peptídeo em sua superfície. De vez em quando, o julgamento acaba sendo um caso de identidade equivocada. A autoimunidade é um desses fenômenos.
Mignot acha que o DR4 está envolvido no que tem sido chamado de “autoimunidade protetora”: um certo peptídeo que o DR4 sabe como agarrar e exibir é na verdade um segmento quimicamente modificado de uma proteína normal que nossas células produzem – tau. É a modificação química que está causando problemas.
A conexão tau?
Observando os efeitos benéficos do DR4 nos níveis de tau e nas patologias tanto no Alzheimer quanto no Parkinson, os pesquisadores se concentraram na tau. Eles cortaram moléculas da proteína em 482 peptídeos, abrangendo coletivamente toda a sequência da tau, e depois os colocaram em pratos separados junto com o produto proteico do DR4 (também chamado de DR4) para ver se ele se liga fortemente a algum desses peptídeos.
Além disso, os pesquisadores testaram todas as modificações químicas biologicamente prováveis que cada um desses peptídeos pode acumular depois de produzidos dentro de uma célula.
DR4 exerceu um controle especialmente poderoso sobre um único peptídeo. Chamado PHF6, este segmento da proteína tau é frequentemente alterado nos cérebros dos pacientes com Alzheimer por uma alteração chamada acetilação – a fixação de um pequeno aglomerado químico a um dos blocos de construção constituintes da proteína nesse segmento. O PHF6 acetilado já foi implicado na tendência das moléculas de tau de se agregarem em emaranhados neurofibrilares.
"O único peptídeo ao qual o DR4 se ligou fortemente foi o PHF6 - e somente quando esse peptídeo foi acetilado", disse Mignot. Já se sabe que a acetilação do PHF6 facilita a agregação da tau em emaranhados neurofibrilares, observou ele.
A acetilação pode “enganar” o sistema imunológico fazendo-o pensar que o PHF6 é um estrangeiro e uma ameaça, disse Mignot, levando o sistema imunológico a atacar e demolir emaranhados neurofibrilares incipientes.
Ele acha que pode ser possível fazer com que o DR4 funcione mais naqueles que o carregam, criando uma vacina composta por PHF6 acetilado. Ao chamar a atenção do sistema imunológico para este peptídeo modificado, tal vacina pode interferir na agregação da tau. Em pessoas que carregam qualquer uma das variantes protetoras do DR4 (nem todas são protetoras) e cujos cérebros começaram a acumular agregados de tau, uma vacina poderia atrasar o início ou retardar a progressão da doença de Alzheimer e possivelmente da doença de Parkinson, sugeriu Mignot.
Pessoas que não são portadoras de DR4 não se beneficiariam com esta vacina, observou Mignot. Além disso, o DR4 vem num espectro de subtipos, distinguidos por minúsculas diferenças na sua sequência genética. Dos seis ou sete subtipos mais comuns de DR4, um pode ser mais comum entre pessoas de uma ascendência, enquanto outros podem ser mais dominantes em pessoas de outras ascendências. O subtipo DR4 mais comum entre os asiáticos orientais não parece ajudar tanto a evitar doenças neurodegenerativas como os subtipos DR4 mais comuns em outras populações, por exemplo.
Um exame de sangue deveria ser feito para ver quem deveria ou não ser vacinado, disse Mignot.
O escritório de licenciamento de tecnologia da Universidade de Stanford apresentou um pedido de patente de propriedade intelectual associado às descobertas deste estudo.
Cerca de 160 investigadores adicionais de outras instituições em cerca de 25 países contribuíram para o trabalho.
Mais informações: Yann Le Guen et al, Análise multiancestral do locus HLA nas doenças de Alzheimer e Parkinson revela uma resposta imune adaptativa compartilhada mediada pelos subtipos HLA-DRB1*04, Proceedings of the National Academy of Sciences (2023 ) . DOI: 10.1073/pnas.2302720120
Informações do jornal: Proceedings of the National Academy of Sciences