Biology subjects

Farache, D.

Publications and source records attributed to Farache, D..

2 recordsLinked to original sources

bioRxiv2023

Autism candidate gene rbm-26 (RBM26/27) regulates MALSU-1 to protect against mitochondrial dysfunction during axon development.

Mitochondrial dysfunction is thought to be a key component of neurodevelopmental disorders such as autism, intellectual disability, and 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 C. 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 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.

neuroscience↗

bioRxiv2020

A stable core of GCPs 4, 5 and 6 promotes the assembly of γ-tubulin ring complexes

{gamma}-tubulin is a major protein involved in the nucleation of microtubules in all eukaryotes. It forms two different complexes with proteins of the GCP family (gamma-tubulin complex proteins): {gamma}-tubulin small complexes ({gamma}TuSCs), containing {gamma}-tubulin and GCPs 2 and 3, and {gamma}-tubulin ring complexes ({gamma}TuRCs), containing multiple {gamma}TuSCs, in addition to GCPs 4, 5, and 6. Whereas the structure and assembly properties of {gamma}TuSCs have been intensively studied, little is known about the assembly of {gamma}TuRCs, and about the specific roles of GCPs 4, 5, and 6. Here, we demonstrate that two copies of GCP4 and one copy each of GCP5 and GCP6 form a salt-resistant sub-complex within the {gamma}TuRC that assembles independently of the presence of {gamma}TuSCs. Incubation of this sub-complex with cytoplasmic extracts containing {gamma}TuSCs leads to the reconstitution of full-sized {gamma}TuRCs that are competent to nucleate microtubules. In addition, we investigate sequence extensions and insertions that are specifically found at the amino-terminus of GCP6, and between the GCP6 grip1 and grip2 motifs, and we demonstrate that these are involved in the assembly or stabilization of the {gamma}TuRC. Summary statement{gamma}-tubulin ring complexes are templates for microtubule nucleation, composed of {gamma}-tubulin and GCP proteins. GCPs 4, 5, 6 form a stable sub-complex, driving the assembly of the full complex.

cell biology↗