Investigating Protein Colocalization with FMRP in Fragile X Syndrome Through Fruit Fly Neuronal and Somatic Models

Abstract

Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disability, yet no treatments currently address the underlying molecular dysfunction. This defect primarily arises from the loss of Fragile X Messenger Ribonucleoprotein (FMRP) production and expression. Although FMRP and its binding partners have been extensively characterized, the functional relevance of many associated proteins, including Synapsin and CK1α, remain incompletely understood. In this study, colocalization analyses revealed that both Synapsin and CK1α show stronger association with FMRP in unstressed cells. Under stress, Synapsin was more diffusely distributed throughout the cytoplasm rather than concentrated within stress granules, indicating that its spatial relationship with FMRP is context-dependent and sensitive to cellular stress. In contrast, CK1α maintains substantial overlap with FMRP under stress, suggesting a more consistent association that is relatively resistant to changes in cellular conditions. These differential colocalization patterns refine our understanding of FMRP-associated regulatory networks and highlight the value of distinguishing transient versus stable protein associations. While this study does not establish causation, CK1α emerges as a promising candidate for future mechanistic investigations to determine whether it directly influences FMRP function or stress granule dynamics. Overall, these findings underscore the importance of stress-responsive FMRP interactions in the molecular pathology of Fragile X Syndrome and provide a framework for further functional studies.