Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition.

Myotonic dystrophy type 2 (DM2), caused by CCTG repeat expansion, is a common adult-onset disorder characterized by myotonia and progressive muscle degeneration with no effective treatment. Here, we identified Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a novel modifier for DM2 therapeutic intervention through a high-throughput chemical screening of 2160 compounds. Moreover, we detailed how both genetic and pharmacological inhibition of TDP1 translates to a cascade of beneficial effects, including improved motor functions, amelioration of progressive muscle degeneration, repair of muscle fiber damage, and normalization of aberrant molecular pathology. Remarkably, the TDP1 inhibition led to substantial CCTG repeat contractions, a mechanism that underlies the observed muscle toxicity and neurodegeneration. Our results highlighted the potential of TDP1 as a molecular target for addressing the complex interplay between repeat expansions and neuromuscular degeneration in DM2, hinting at broader applicability in a spectrum of repeat expansion disorders.