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Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition
Yingbao Zhu1, Shengwei Xiao1, Xinxin Guan1
1Furong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Abstract:
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.
Insights
Researchers identified Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a potential therapeutic target for myotonic dystrophy type 2 (DM2). Inhibiting TDP1 improved muscle function and reduced toxic repeat expansions in DM2 models.
Area of Science:
- Neurology
- Genetics
- Molecular Biology
Background:
- Myotonic dystrophy type 2 (DM2) is an adult-onset genetic disorder caused by CCTG repeat expansions, leading to myotonia and muscle degeneration.
- Current treatments for DM2 are ineffective, necessitating the exploration of novel therapeutic targets.
Purpose of the Study:
- To identify novel therapeutic targets for myotonic dystrophy type 2 (DM2) through high-throughput chemical screening.
- To investigate the role of Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a potential therapeutic intervention for DM2.
Main Methods:
- Conducted a high-throughput chemical screen of 2160 compounds to identify DM2 modifiers.
- Utilized genetic and pharmacological inhibition of TDP1 in DM2 models.
- Assessed motor functions, muscle degeneration, muscle fiber repair, and molecular pathology.
Main Results:
- Identified Tyrosyl-DNA phosphodiesterase 1 (TDP1) as a novel therapeutic target for DM2.
- Demonstrated that TDP1 inhibition improves motor function and ameliorates muscle degeneration.
- Observed repair of muscle fiber damage and normalization of molecular pathology following TDP1 inhibition.
- Showcased significant CCTG repeat contractions upon TDP1 inhibition, a key factor in DM2 pathology.
Conclusions:
- TDP1 inhibition represents a promising therapeutic strategy for myotonic dystrophy type 2 (DM2).
- Targeting TDP1 addresses the core mechanisms of CCTG repeat expansions and subsequent neuromuscular degeneration.
- The findings suggest potential broader applications of TDP1 inhibition in other repeat expansion disorders.
