Avoiding the Pitfalls of Tunnel Vision
In a reward system driven by grant dollars in hand and publication numbers/journal impact factors, it is only too easy to put on the blinders and succumb to tunnel vision. Single-minded focus is a prized career trait in academia. Yet the puzzle that is myotonic dystrophy may only be solved by modelling that benefits from diseases not within the focus of your current R01 or the publication track record that you’re building. The role that Repeat-Associated Non-ATG (RAN) translation plays in DM1/DM2 is likely one of those cases where insights can be defeated by excessive focus on just ‘your disease.’
A Cross-Disease Framework for Understanding RAN Translation
Although studies in DM1 contributed toward the initial identification and characterization of a new molecular phenomenon, RAN translation, its role in the pathogenesis of DM remains elusive. Evidence on RAN translation acquired from ‘other diseases’ may advance understanding of basic and conserved molecular mechanisms, but also may inform what specific role RAN translation plays in DM and whether this mechanism needs to be targeted by therapeutic strategies. A new publication by Dr. Laura Ranum and colleagues at the University of Florida (including a former MDF Fellow as lead author, Dr. John Cleary) sought to review current knowledge of RAN translation across multiple microsatellite expansion disorders of the nervous system (Cleary et al., 2018).
The review article gives a nice synopsis of the discovery and initial characterization of RAN translation in neurological disorders. Initial discovery was in Spinocerebellar ataxia type 8, but the mechanism was also rapidly found in DM1 as appropriate control experiments were included to ensure that RAN proteins could not arise from another mechanism. Discovery and characterization in other diseases rapidly followed, often expanding the potential pathological mechanisms operative in a disease—FXTAS being a prominent example where the field had pushed a toxic RNA gain of function mechanism, but now toxic RAN proteins had to be considered as well. By contrast, toxic polyglutamine proteins have been a leading pathogenic mechanism in Huntington’s disease, but it was soon discovered that CAG repeats in canonical open reading frames yielded multiple RAN proteins. RAN translation was subsequently discovered in other diseases where MBNL sequestration had been linked to the disease mechanism—DM2 and Fuch’s Endothelial Corneal Dystrophy. Finally, the authors devote space to the extensive work in C9orf72 ALS/FTD, where the literature now implicates RAN translation in specific molecular roles that may contribute to disease.
The authors of this review also discuss targeting of the RAN translation mechanism in drug discovery and development efforts. They note that such strategies may facilitate the determination of the differential roles of RNA gain-of-function versus RAN translation proteins.
It’s encouraging that many DM researchers have ties to the broader microsatellite expansion disorder community and attend conferences with that distributed agenda. Thus, there’s already a strong inclination to avoid the blinders and seek understanding of how similarities and differences across this > 40 neurological disease class with repeat expansions (8 of which have now been reported to exhibit RAN proteins) can provide insights into the individual diseases. Finally, it’s important to remember that both laser-like focus on DM and attention to lessons from the broader neurological disease class that invokes similar mechanisms may represent the optimal path forward to help patients living with DM.
Repeat associated non-ATG (RAN) translation.
Cleary JD, Pattamatta A, Ranum LPW.
J Biol Chem. 2018 Sep 13. pii: jbc.R118.003237. doi: 10.1074/jbc.R118.003237. [Epub ahead of print]