A novel form of disease pathogenesis, in which cell damage is caused by transcripts with expanded CUG repeats, has been described in myotonic dystrophy type 1 (DM1). Our group recently described another disorder, Huntington's disease-like 2 (HDL2), that is also associated with CUG repeat toxicity. Like DM1, HDL2 is a dominant disorder. Unlike DM1, HDL2 is very similar to Huntington's disease (HD), with mid-life onset of a devastating neurodegenerative process selectively affecting the striatum and cerebral cortex and progressing inevitably to death. We found that HDL2 is caused by a CAG/CTG repeat expansion in junctophilin-3 (JPH3) on chromosome 16q24.3, and that JPH3 transcripts with an expanded repeat accumulate and form foci in neuronal nuclei. Preliminary cell experiments suggest that these transcripts are toxic, and may induce toxicity via redistribution of muscleblind-like protein 1 (MBNL1), a protein also implicated in the muscle and brain abnormalities of DM1. Surprisingly, our preliminary experiments indicate that untranslated huntingtin transcripts containing CAG repeat expansions are also toxic. These preliminary findings have led us to hypothesize that the pathogenesis of HDL2, and perhaps HD, may at least partly stem from transcripts with expanded repeats. More specifically, we hypothesize that RNA-induced neurotoxicity will be determined by the type and length of the repeat, the sequence flanking the repeat, and the cell types in which the repeat is expressed. We also hypothesize that the pathogenesis of this neurotoxicity will involve the splice-regulating protein muscleblind like 1 (MBNL1). Here, we propose to develop and explore cell models that will provide clues about RNA neurotoxicity in both CUG and CAG diseases. If successful, our work will open up new lines of investigation into the pathogenesis of HDL2, HD, and potentially other repeat disorders, with the ultimate goal of developing new targets for the therapeutics of neurodegenerative disease.
Several diseases that affect the brain are caused, at least in part, by mutant RNA molecules that contain abnormally long tracts of repeating units. In this project, we seek to determine how these RNA molecules cause brain injury by a series of experiments using cultured brain cells. The purpose is to find molecular targets that may be amenable to therapeutic intervention.
| Margolis, Russell L; Rudnicki, Dobrila D (2016) Pathogenic insights from Huntington's disease-like 2 and other Huntington's disease genocopies. Curr Opin Neurol 29:743-748 |
| Seixas, Ana I; Holmes, Susan E; Takeshima, Hiroshi et al. (2012) Loss of junctophilin-3 contributes to Huntington disease-like 2 pathogenesis. Ann Neurol 71:245-57 |
| Chung, Daniel W; Rudnicki, Dobrila D; Yu, Lan et al. (2011) A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression. Hum Mol Genet 20:3467-77 |
