Several neurodegenerative disorders, including Huntington?s disease (HD), are caused by the expansion of a CAG nucleotide repeat. For many years, it has been hypothesized that the translation of this CAG sequence into a poly-glutamine (polyQ) protein represents the molecular basis for these diseases. However, in some cases, patients carrying expanded CAG repeats exhibit significant neurodegeneration in the absence of detectable polyQ protein, suggesting other polyQ-independent mechanisms might contribute to HD. The nature of such polyQ-independent toxicity in CAG repeat disorders is unknown. Recent work demonstrated that Huntington?s associated CAG repeats can undergo an unusual type of translation called Repeat Associated non-AUG-dependent (RAN) translation. In RAN translation, both sense (CAG)x and antisense (CTG)x repeats are translated in all three reading frames to produce five distinct RAN peptides. RAN peptides are detected in HD patients with CAG repeat expansions but not in control patients that lack expansions. Several RAN peptides are present in brain regions that undergo neurodegeneration in HD but that lack detectable polyQ, suggesting that RAN peptides make significant polyQ-independent pathological contributions to HD. To better understand the pathological potential of HD RAN peptides, we generated C. elegans models for each individual RAN peptide. We found that several RAN peptides form protein aggregates that are distinct from well-described polyQ aggregates. At least one of these new RAN peptides exhibits toxicity that rivals that of polyQ when expressed in C. elegans. In this project, we will use the significant experimental advantages of C. elegans to rapidly characterize these new HD RAN peptides and determine if they share similar mechanisms of toxicity with the better understood polyQ proteins. Our studies will define clinically relevant mechanisms that facilitate HD RAN peptide neurotoxicity, some of which might be leveraged to treat or better diagnose this currently incurable diseases.
For years, it was thought that a polyglutamine protein derived from the translation of the CAG repeat expansion in the Huntingtin gene represented the major cause of Huntington?s disease. However, it was recently discovered that CAG repeats can be translated in multiple reading frames in both sense and antisense directions to produce five different peptides, including polyglutamine, that are found only in HD patients. Our studies will define clinically relevant mechanisms that allow these newly discovered HD peptides to cause neurodegeneration, some of which might be leveraged to treat or better diagnose this currently incurable diseases.
