Molecular Repositioning of Celecoxib as a Neurotherapeutic Agent in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

Fragile X-associated tremor/ataxia syndrome (FXTAS), a nucleotide repeat expansion disorder, arises from CGG repeat expansions in the 5' untranslated region (UTR) of the <i>fragile X messenger ribonucleoprotein 1 (FMR1)</i> gene, leading to RNA foci formation and toxic protein aggregation via repeat-associated non-AUG (RAN) translation. These fundamental mechanisms often lead to a series of consequences, including splicing defects, neuroinflammation, mitochondrial dysfunction, impaired autophagy, and cell death. Targeting toxic RNA repeats offers a promising therapeutic strategy. In this study, we identified Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, as a potential treatment for FXTAS. At first, we utilized various biophysical assays and molecular docking to confirm Celecoxib's strong binding affinity toward the r-(CGG)_exp RNA. Further studies in the cellular model demonstrated the potency of Celecoxib in reducing toxic protein aggregates and improving splicing defects. Notably, it significantly reduces FMR1PolyG aggregates in the <i>Drosophila</i> FXTAS model, leading to improved locomotor impairments and the mitigation of associated downstream pathological consequences. Moreover, Celecoxib treatment significantly extends the lifespan of the flies. Thus, these results collectively support the therapeutic potential of repurposing Celecoxib for the treatment of FXTAS.