UC San Diego

In 2011, two independent groups discovered that hexanucleotide repeat expansion in C9orf72 cause amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Since this paramount discovery, a race has ensued to understand the mechanisms underlying neurodegeneration and develop a cure for this fatal disease. Bidirectional transcription of C9orf72 complicates gain of function toxicity and treatment. Both sense and antisense RNA can be toxic as repeat-containing RNA and when translated into dipeptide repeat proteins (DPRs). Perhaps due to the gap between identifying C9orf72 repeat expansion and bidirectional transcription, the field has mainly focused on unravelling disease mechanisms involving toxicity from sense RNA and sense-encoded DPRs, and contributions from antisense RNA are less well understood.

However, the relatively few studies that have investigated the role of antisense RNA in disease have found evidence that it is important in toxicity and perhaps an important target for effective treatment. Both sense and antisense RNA form peri-nucleolar RNA foci, but unlike sense RNA, peri-nucleolar antisense RNA foci are intrinsically related to pathology. Peri-nucleolar antisense but not sense RNA foci are significantly increased in regions vulnerable to neurodegeneration and correlate with clinical symptoms of FTD. Moreover, increased peri-nucleolar antisense but not sense RNA foci correlate with TAR DNA binding protein (TDP-43) mislocalization, the hallmark proteinopathy of C9-ALS/FTD. Additionally, morphological alterations comprising shrunken nucleoli, nuclei and cytoplasm occur in C9-ALS and sporadic ALS spinal motor neurons, but perplexingly, these alterations occur in the absence of peri-nucleolar antisense RNA foci or TDP-43 mislocalization. This raises the possibility that nucleolar antisense RNA foci formation and TDP-43 mislocalization occur later in disease following morphological abnormalities. Nevertheless, antisense RNA may be toxic before forming peri-nucleolar RNA foci and may remain a key target for effective therapy. Thus, disease-relevant phenotypes in cellular models, such as C9orf72 patient fibroblasts, may prove useful to measure the benefits of reducing potential gain of function toxicity from the C9orf72 sense and antisense strands.