Ortholog of autism candidate gene RBM27 regulates mitoribosomal assembly factor MALS-1 to protect against mitochondrial dysfunction and axon degeneration during neurodevelopment.

Autor:	Chowdhury, Tamjid A., Luy, David A., Scapellato, Garrett, Farache, Dorian, Lee, Amy S. Y., Quinn, Christopher C.
Předmět:	GENE expression ATTENTION-deficit hyperactivity disorder RNA-binding proteins MISSENSE mutation INTELLECTUAL disabilities
Zdroj:	PLoS Biology; 10/31/2024, Vol. 22 Issue 10, p1-29, 29p
Abstrakt:	Mitochondrial dysfunction is thought to be a key component of neurodevelopmental disorders such as autism, intellectual disability, and attention-deficit hyperactivity disorder (ADHD). However, little is known about the molecular mechanisms that protect against mitochondrial dysfunction during neurodevelopment. Here, we address this question through the investigation of rbm-26, the Caenorhabditis elegans ortholog of the RBM27 autism candidate gene, which encodes an RNA-binding protein whose role in neurons is unknown. We report that RBM-26 (RBM26/27) protects against axonal defects by negatively regulating expression of the MALS-1 (MALSU1) mitoribosomal assembly factor. Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression along with defects in axon overlap and axon degeneration that occurs during larval development. Using a biochemical screen, we identified the mRNA for the MALS-1 mitoribosomal assembly factor as a binding partner for RBM-26. Loss of RBM-26 function causes a dramatic overexpression of mals-1 mRNA and MALS-1 protein. Moreover, genetic analysis indicates that this overexpression of MALS-1 is responsible for the mitochondrial and axon degeneration defects in rbm-26 mutants. These observations reveal a mechanism that regulates expression of a mitoribosomal assembly factor to protect against axon degeneration during neurodevelopment. Mitochondrial dysfunction contributes to neurodevelopmental disorders, such as autism or ADHD. This study shows that an ortholog of an autism-candidate gene protects against axonal defects by negatively regulating the expression of the mitoribosomal assembly factor MALS-1. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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