Molecular and cellular basis of hyperassembly and protein aggregation driven by a rare pathogenic mutation in DDX3X

Autor(es):Mostrar menos -

Fonseca, Matheus de Castro ^[1] ; de Oliveira, Juliana Ferreira ^[1] ; Silva Araujo, Bruno Henrique ^[1] ; Canateli, Camila ^[1] ; Vital do Prado, Paula Favoretti ^[1] ; Amorim Neto, Dionisio Pedro ^{[2, 1]} ; Bosque, Beatriz Pelegrini ^{[2, 1]} ; Rodrigues, Paulla Vieira ^{[2, 1]} ; Pereira de Godoy, Joao Vitor ^{[2, 1]} ; Tostes, Katiane ^[1] ; Ribeiro Filho, Helder Veras ^[1] ; Ziem Nascimento, Andrey Fabricio ^[3] ; Saito, Angela ^[1] ; Costa Tonoli, Celisa Caldana ^[1] ; Heleno Batista, Fernanda Aparecida ^[1] ; Lopes de Oliveira, Paulo Sergio ^[1] ; Figueira, Ana Carolina ^[1] ; da Costa, Silvia Souza ^[4] ; Victorino Krepischi, Ana Cristina ^[4] ; Rosenberg, Carla ^[4] ; Westfahl, Jr., Harry ^[3] ; Roque da Silva, Antonio Jose ^[3] ; Franchini, Kleber Gomes ^{[1, 5]}

Afiliação do(s) autor(es)

^[1] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, 10000 Giuseppe Maximo Scolfaro St, BR-13083100 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Dept Struct & Funct Biol, Campinas - Brazil

^[3] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Synchrotron Light Natl Lab LNLS, Campinas - Brazil

^[4] Univ Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, Sao Paulo, SP - Brazil

^[5] Univ Estadual Campinas, Sch Med, Dept Internal Med, Campinas - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ISCIENCE; v. 24, n. 8 AUG 20 2021.
• Citações Web of Science: 0

Resumo

Current studies estimate that 1-3% of females with unexplained intellectual disability ( ID) present de novo splice site, nonsense, frameshift, or missense mutations in the DDX3X protein (DEAD-Box Helicase 3 X-Linked). However, the cellular and molecular mechanisms by which DDX3X mutations impair brain development are not fully comprehended. Here, we show that the ID-linked missense mutation L556S renders DDX3X prone to aggregation. By using a combination of biophysical assays and imaging approaches, we demonstrate that this mutant assembles solid-like condensates and amyloid-like fibrils. Although we observed greatly reduced expression of the mutant allele in a patient who exhibits skewed X inactivation, this appears to be enough to sequestrate healthy proteins into solid-like ectopic granules, compromising cell function. Therefore, our data suggest ID-linked DDX3X L556S mutation as a disorder arising from protein misfolding and aggregation. (AU)

• Processo FAPESP: 18/20014-0 - Conectando o intestino e o cérebro: envolvimento do microbioma intestinal no surgimento e progressão da doença de Parkinson esporádica
• Beneficiário: Matheus de Castro Fonseca
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/24511-0 - LRRK2 e Rab GTPases na neurodegeneração causada pela Doença de Parkinson esporádica
• Beneficiário: Beatriz Pelegrini Bosque
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs