Biology subjects

Moine, H.

Publications and source records attributed to Moine, H..

6 recordsLinked to original sources

bioRxiv2026

The DGKK mRNA is a primary target of the Prader-Willi syndrome-associated snoRNA SNORD116

Box C/D small nucleolar RNAs (SNORDs) classically guide site-specific modification of ribosomal RNAs through antisense elements located upstream of their D[prime] and D boxes, termed ASE1 and ASE2. Yet many orphan SNORDs have no established primary targets, including the paternally expressed multicopy SNORD116 family implicated in Prader-Willi syndrome. Our previous comparative analysis identified the DGKK/Dgkk interaction as the most evolutionarily persistent candidate involving the highly conserved SNORD116 ASE1 sequence and showed that SNORD116 depletion increases DGKK RNA abundance in human cells. Here, we re-evaluated this interaction alongside a focused set of recently published candidates and asked whether evolutionary persistence was accompanied by independent evidence of regulation. DGKK/Dgkk showed reproducible increases following transient SNORD116 loss across human iPSC-derived neural cells and in brain tissues from Snord116-knockout mice. Its predicted SNORD116 interaction site combined a marked local depletion of human sequence variation with an overlapping cis-regulatory interval identified in mouse. SNORD116 deficiency was also associated with increased endogenous DGK[kappa]; protein across several mouse brain regions, including the hypothalamus. More broadly, comparison across the candidate set showed that evolutionary persistence, duplex stability and expression response did not systematically align, indicating that sequence-based properties alone do not allow reliable prediction of responses to SNORD116 loss. Together, these data support DGKK/Dgkk as the best-supported primary regulatory target of SNORD116 to date and establish it as a model for dissecting the regulatory mechanism of this orphan snoRNA family.

molecular biology↗

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

Comparative analysis of PDZ-binding motifs in the diacylglycerol kinase family

Diacylglycerol kinases (DGKs) control local and temporal amounts of diacylglycerol (DAG) and phosphatidic acid (PA) by converting DAG to PA through phosphorylation in cells. Certain DGK enzymes possess C-terminal sequences that encode potential PDZ-binding motifs (PBMs), which could be involved in their recruitment into supramolecular signaling complexes. In this study, we used two different interactomic approaches, quantitative native holdup (nHU) and qualitative affinity purification (AP), both coupled to mass spectrometry (MS) to investigate the PDZ partners associated with the potential PBMs of DGKs. Complementing these results with site-specific affinity interactomic data measured on isolated PDZ domain fragments and PBM motifs, as well as evolutionary conservation analysis of the PBMs of DGKs, we explored functional differences within different DGK groups. All our results indicate that putative PBM sequences of type II enzymes are likely to be nonfunctional. In contrast, type IV enzymes possess highly promiscuous PBMs that interact with a set of PDZ proteins with very similar affinity interactomes. The combination of various interactomic assays and evolutionary analyses provides a useful strategy for identifying functional domains and motifs within diverse enzyme families.

molecular biology↗

bioRxiv2021

AAV-delivery of diacylglycerol kinase kappa achieves long-term rescue of Fmr1-KO mouse model deficits of fragile X syndrome

Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. It results from the lack of the RNA binding protein FMRP and is associated with the overactivation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk) is a main mRNA target of FMRP in cortical neurons. Here we show that diacylglycerol kinase kappa (DGKk), when modified as to become FMRP-independent and delivered into the brain of adolescent mice using adeno-associated viral vectors, corrects brain diacylglycerol and phosphatidic acid homeostasis and the main phenotypic behaviors of the Fmr1-KO mouse model of FXS. Thus, DGKk appears as a key triggering factor of FXS pathomechanism while providing a possible means of intervention for FXS gene therapy. One sentence summaryDGKk gene therapy in Fmr1-KO mouse model

neuroscience↗

bioRxiv2020

Pioglitazone improves deficits of Fmr1-KO mouse model of Fragile X syndrome by interfering with excessive diacylglycerol signaling

Fragile X syndrome (FXS), the leading cause of familial intellectual disability, is an uncured disease caused by the absence or loss of function of the FMRP protein. FMRP is an RNA binding protein that controls the translation of specific proteins in neurons. A main target of FMRP in neurons is diacylglycerol kinase kappa (DGKk) and the loss of FMRP leads to a loss of DGK activity causing a diacylglycerol excess in the brain. Excessive diacylglycerol signaling could be a significant contributor to the pathomechanism of FXS. Here we tested the contribution of DAG-signaling in Fmr1-KO mouse model of FXS and we show that pioglitazone, a widely prescribed drug for type 2 diabetes, has ability to correct excessive DAG signaling in the brain and rescue behavioral alterations of the Fmr1-KO mouse. This study highlights the role of lipid signaling homeostasis in FXS and provides arguments to support the testing of pioglitazone for treatment of FXS.

neuroscience↗

bioRxiv2019

Spatial control of nucleoporin assembly by Fragile X-related proteins

Nucleoporins (Nups) build highly organized Nuclear Pore Complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve-like hydrogel within the central channel of the NPCs to regulate nucleocytoplasmic exchange. In the cytoplasm, a large excess of soluble Nups has been reported, but how their assembly is restricted to the NE is currently unknown. Here we show that Fragile X-related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule and dynein-dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and Fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup protein condensates. Likewise, several models of Fragile X syndrome (FXS), characterized by a loss of FMRP, also accumulate cytoplasmic Nup aggregates. These aggregate-containing cells display aberrant nuclear morphology and a delay in G1 cell cycle progression. Our results reveal an unexpected role for the FXR protein family and dynein in the spatial regulation of nucleoporin assembly.\n\nHighlightsCytoplasmic nucleoporins are assembled by Fragile X-related (FXR) proteins and dynein\n\nFXR-Dynein pathway downregulation induces aberrant cytoplasmic aggregation of nucleoporins\n\nCellular models of Fragile X syndrome accumulate aberrant cytoplasmic nucleoporin aggregates.\n\nFXR-Dynein pathway regulates nuclear morphology and G1 cell cycle progression\n\neTOC BlurbNucleoporins (Nups) form Nuclear Pore Complexes (NPCs) at the nuclear envelope. Agote-Aran at al. show how cells inhibit aberrant assembly of Nups in the cytoplasm and identify Fragile X-related (FXR) proteins and dynein that facilitate localization of Nups to the nuclear envelope and control G1 cell cycle progression.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC=\"FIGDIR/small/767202v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (29K):\norg.highwire.dtl.DTLVardef@14a684borg.highwire.dtl.DTLVardef@53670org.highwire.dtl.DTLVardef@391907org.highwire.dtl.DTLVardef@9a290a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract\n\nC_FIG

cell biology↗