Probing nucleolus function in a mouse model of fragile X syndrome

Fragile X syndrome (FXS) stands as a prominent contributor to intellectual disability and autism spectrum disorders, stemming from mutations within the FMR1 gene. These mutations lead to severe reduction or absence of the FMRP protein. Despite extensive research, effective medical interventions for FXS remain elusive, hindered by a limited understanding of its underlying mechanisms. Biochemical investigations have consistently highlighted FMRP's role in modulating mRNA translation, with its absence correlating with increased translation levels of select FMRP- interacting mRNA targets. However, emerging evidence suggests broader dysregulation, as FXS neurons exhibit heightened overall protein synthesis, hinting at elevated translation of non-FMRP interacting mRNAs. This intriguing phenomenon underscores the need for a deeper exploration into the cellular dysfunctions characterizing FXS. This research initiative aims to unravel a novel facet of FXS pathology—nucleolar hyper-function. We propose that this hyper-function contributes to aberrant ribosome biogenesis, thus augmenting the cellular capacity for translation and driving the observed global increase in protein synthesis in FXS. Aim 1 will assess neuronal and glial nucleolar function in wild-type (WT) and Fmr1 knockout (KO) mice. Aim 2 will conduct a comparative analysis of genome-wide proteomic data encompassing nucleolar proteins in WT and Fmr1 KO samples, discerning molecular alterations integral to ribosome biogenesis and assembly. Aim 3 will assess nucleolar function in the peripheral tissue in Fmr1 KO mice, establishing the hyper-functional pathological outcome as a potential clinical biomarker. The successful execution of this exploratory R21 project promises to unveil previously unexplored cellular mechanisms underlying FXS pathology. This study will also suggest nucleolus-associated abnormalities as novel molecular/cellular measures and potential biomarkers. Project Number: 1R21MH140167-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Hongbing Wang | Institution: MICHIGAN STATE UNIVERSITY, EAST LANSING, MI | Award Amount: $416,859 | Activity Code: R21 | Study Section: Developmental Brain Disorders Study Section[DBD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11302926