CRISPR activation of the ribosome-associated quality control factor ASCC3 ameliorates fragile X syndrome phenotypes in mice

ABSTRACT: Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism-spectrum disorder. Despite the prevalence of the FXS, the molecular function of FMRP remains uncertain. Here, we showed that FMRP regulates collided ribosomes. Activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor, was identified as an FMRP-interacting protein. Mechanistically, FMRP recruits ASCC3 to collided ribosomes and either positively or negatively regulates translation, depending on transcript context. Disease-associated ASCC3 variants that perturbed ASCC3-FMRP interaction were defective in ribosome association and handling of collided ribosomes. In FXS patient cells and mouse models of FXS, ASCC3 abundance was reduced, and Clustered Regularly Interspaced Short Palindromic Repeats-mediated activation (CRISPRa) of ASCC3 overcame challenges to conventional gene delivery approaches presented by the sheer size of ASCC3 and rescued synaptic defects and behavioral deficits. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and showed. Proof-of-concept that targeting RQC may offer alternative treatment strategies for FXS.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Keratinocyte

DISEASE(S): Fragile X Syndrome

SUBMITTER: JI Geng  

LAB HEAD: Bingwei Lu

PROVIDER: PXD067852 | Pride | 2026-04-20

REPOSITORIES: Pride