Fragile X syndrome-linked mutations impair FMRP accumulation in neuronal transport granules
- 1Yokohama City University
Abstract
RNA granules are biomolecular condensates that are reversibly formed through multivalent interactions among mRNAs and RNA-binding proteins (RBPs). RNA granules include stress granules and neuronal transport granules, which share common components and functions in translational regulation. Fragile X messenger ribonucleoprotein (FMRP) is an RBP encoded by FMR1, whose loss of function causes fragile X syndrome (FXS), a neurodevelopmental disorder. FMRP is a component of both stress granules and neuronal transport granules. Although several FXS-associated missense mutations in FMRP have been identified, it remains unclear whether these mutations affect the assembly of FMRP into RNA granules. Here, we found that the KH1 domain mutation G266E markedly reduced the accumulation of FMRP in stress granules in HEK293T cells, whereas the KH2 domain mutation I304N had little effect. In addition, both G266E and I304N reduced the accumulation of FMRP within neuronal transport granules in FMRP-deficient mouse cortical neurons. Because G266E and I304N have been reported to impair the RNA-binding and/or RNA-associated functions of FMRP, our findings suggest that the KH1 and KH2 domains are important for the assembly of FMRP into RNA granules. These findings further raise the possibility that impaired RNA granule assembly may contribute to the pathogenesis of FXS and other neurodevelopmental disorders.
Related
- Accumulation of FAM98B and tRNA-Splicing Ligase Complex Proteins in Neuronal Intranuclear Inclusions in Spinocerebellar ataxia type 4.
- Somatic mutations and single-nucleus transcriptomics reveal uniquely human properties of neuronal aging
- Excessive cholesterol accumulation in microglia increases neuronal synaptic vulnerability to amyloid-beta
- Single Cell Proteomics reveals partial uncoupling of the Glycerol-3-Phosphate shuttle to compensate for Electron Transport Chain dysfunction in Alexander Disease GFAP mutations
- Butyrate Regulates the Blood–Brain Barrier Transport and Intraendothelial Accumulation of Alzheimer’s Disease Amyloid-Beta Peptides
BibTeX
@misc{kubo2026fragile,
title = {{Fragile X syndrome-linked mutations impair FMRP accumulation in neuronal transport granules}},
author = {M. Kubo and M. Ishiyama and K. Yoshizawa and Y. Sasaki},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.750051},
url = {https://www.biorxiv.org/content/10.64898/2026.09.08.750051v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Fragile X syndrome-linked mutations impair FMRP accumulation in neuronal transport granules
AU - M. Kubo
AU - M. Ishiyama
AU - K. Yoshizawa
AU - Y. Sasaki
PY - 2026
DA - 2026/09/08
PB - bioRxiv
DO - 10.64898/2026.09.08.750051
UR - https://www.biorxiv.org/content/10.64898/2026.09.08.750051v1
AB - RNA granules are biomolecular condensates that are reversibly formed through multivalent interactions among mRNAs and RNA-binding proteins (RBPs). RNA granules include stress granules and neuronal transport granules, which share common components and functions in translational regulation. Fragile X messenger ribonucleoprotein (FMRP) is an RBP encoded by FMR1, whose loss of function causes fragile X syndrome (FXS), a neurodevelopmental disorder. FMRP is a component of both stress granules and neuronal transport granules. Although several FXS-associated missense mutations in FMRP have been identified, it remains unclear whether these mutations affect the assembly of FMRP into RNA granules. Here, we found that the KH1 domain mutation G266E markedly reduced the accumulation of FMRP in stress granules in HEK293T cells, whereas the KH2 domain mutation I304N had little effect. In addition, both G266E and I304N reduced the accumulation of FMRP within neuronal transport granules in FMRP-deficient mouse cortical neurons. Because G266E and I304N have been reported to impair the RNA-binding and/or RNA-associated functions of FMRP, our findings suggest that the KH1 and KH2 domains are important for the assembly of FMRP into RNA granules. These findings further raise the possibility that impaired RNA granule assembly may contribute to the pathogenesis of FXS and other neurodevelopmental disorders.
ER -