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

Author(s):Show less -

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]}

Affiliation

^[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

• Document type: Journal article
• Source: ISCIENCE; v. 24, n. 8 AUG 20 2021.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 18/20014-0 - The gut-brain connection: role of the gut microbioma in the outcome and development of the sporadic Parkinson's disease
• Grantee: Matheus de Castro Fonseca
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/24511-0 - The role of LRRK2 and Rab GTPases in the neurodegeneration during sporadic Parkinson's Disease
• Grantee: Beatriz Pelegrini Bosque
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC