Biology subjects

PITON, A.

Publications and source records attributed to PITON, A..

3 recordsLinked to original sources

bioRxiv2026

FMRP controls diacylglycerol-dependent neuronal activity by mediating m6A-regulated translation efficiency

Fragile X syndrome (FXS), a leading inherited cause of intellectual developmental disorder and autism, results from loss of the RNA-binding protein FMRP. Loss of FMRP causes excessive neuronal protein synthesis contributing to widespread functional disturbances, yet the mechanisms linking FMRP to specific mRNA targets remain unclear. We show that FMRP promotes translation of the brain mRNA DGK{kappa} by binding mA-modified repetitive RNA motifs, thereby relieving a translational block encoded within its sequence. FMRP loss sharply reduces neuronal DGK{kappa}, and DGK{kappa} depletion alone reproduces hallmark FXS phenotypes, including hyperactivity, compulsive behavior, overgrowth, dendritic spine abnormalities, overactivated diacylglycerol signaling and increased protein synthesis. These findings identify DGK{kappa} as a key effector of FMRP function and establish a regulatory axis where mA RNA modification modulates neuronal translation. This work defines new principles of translational control in neurodevelopmental disorders and positions DGK{kappa} as a central driver of FXS pathogenesis.

molecular biology↗

bioRxiv2023

Modeling neurodevelopmental disorder-associated hAGO1 mutations in C. elegans Argonaute ALG-1

MicroRNAs (miRNA) are endogenous non-coding RNAs important for post-transcriptional regulation of gene expression. miRNAs associate with Argonaute proteins to bind to the 3 UTR of target genes and confer target repression. Recently, multiple de novo coding variants in the human Argonaute gene AGO1 (hAGO1) have been reported to cause a neurodevelopmental disorder (NDD) with intellectual disability (ID). Most of the altered amino acids are conserved between the miRNA-associated Argonautes in H. sapiens and C. elegans, suggesting the hAGO1 mutations could disrupt evolutionarily conserved functions in the miRNA pathway. To investigate how the hAGO1 mutations may affect miRNA biogenesis and/or functions, we genetically modeled four of the hAGO1 de novo variants (referred to as NDD mutations) by introducing the identical mutations to the C. elegans hAGO1 homolog, alg-1. This array of mutations caused distinct effects on C. elegans miRNA functions, miRNA populations, and downstream gene expression, indicative of profound alterations in aspects of miRNA processing and miRISC formation and/or activity. Specifically, we found that the alg-1 NDD mutations cause allele-specific disruptions in mature miRNA profiles both in terms of overall abundances and association with mutant ALG-1. We also observed allele-specific profiles of gene expression with altered translational efficiency and/or mRNA abundance. The sets of perturbed genes include human homologs whose dysfunction is known to cause NDD. We anticipate that these cross-clade genetic studies may advance the understanding of fundamental Argonaute functions and provide insights into the conservation of miRNA-mediated post-transcriptional regulatory mechanisms.

molecular biology↗

bioRxiv2021

Human RNA Nm-MTase FTSJ1: new tRNA targets and role in the regulation of brain-specific genes.

FTSJ1 is a conserved human 2-O-methyltransferase (Nm-MTase) that modifies several transfer RNAs (tRNAs) at position 32 and the wobble position 34 in the AntiCodon Loop (ACL). Its loss of function has been linked to Non-Syndromic X-Linked Intellectual Disability (NSXLID), and more recently to cancers. However, the molecular mechanisms underlying these pathologies are currently unclear. Here we report a novel FTSJ1 pathogenic variant from a NSXLID patient. Using blood cells derived from this patient and other affected individuals carrying FTSJ1 mutations, we performed an unbiased and comprehensive RiboMethSeq analysis to map the ribose methylation (Nm) on all human tRNAs and identify novel targets. In addition, we performed a transcriptome analysis in these cells and found that several genes previously associated with intellectual disability and cancers were deregulated. We also found changes in the miRNA population that suggest potential cross-regulation of some miRNAs with these key mRNA targets. Finally, we show that differentiation of FTSJ1-depleted human neuronal progenitor cells (NPC) into neurons displays long and thin spine neurites compared to control cells. These defects are also observed in Drosophila and are associated with long term memory deficit in this organism. Altogether, our study adds insight into FTSJ1 pathologies in human and flies by the identification of novel FTSJ1 targets and the defect in neuron morphology.

genetics↗