In the pathobiology of neuromuscular disorders, dysregulation of RNA metabolism has emerged as a pivotal factor. This is especially evident in ALS/FTD, where many disease-causing mutations involve RNA-binding proteins (RBPs), leading to malfunctioning mRNA maturation, alternative splicing, and RNA trafficking. The most common genetic form of ALS/FTD is the hexanucleotide repeat expansion in the C9orf72 gene, which produces toxic RNA molecules and dipeptides repeats (DPRs) that sequester key RBPs and subsequently result in widespread changes of the transcriptome.
The RNA exosome complex, the major ribonuclease in mammals, is crucial for the degradation and processing of nearly all RNA species. While the exosome complex is ubiquitously expressed, its activity is essential for motor neuron survival, as loss-of-function mutations in subunits of the exosome complex cause early-onset neurodegenerative diseases characterized by rapid motor neuron degeneration and cerebellar atrophy. Given that subunits of the exosome complex directly interact with RBPs implicated in ALS pathology (e.g., TDP-43, FUS, SETX, Matrin-3), as well as with the dipeptide repeat proteins (DPRs) characteristic of C9orf72-ALS, we investigated the significance of the exosome complex in the context of C9orf72 pathology. We demonstrate that reducing subunits of the exosome complex increases the accumulation of repeat RNA and elevates the levels of RAN-translated DPRs. Conversely, overexpression reversed this phenomenon, resulting in a significant decrease of repeat RNA and DPRs. Moreover, we found evidence that the catalytically active subunit of the exosome complex is reduced in iPSC derived motor neurons from ALS patients and that the presence of DPRs influences the nucleolar localization of the exosome complex. Finally, preliminary results indicate beneficial outcomes in neurological behavioral testing for mice overexpressing exosome subunits in a mouse model of C9orf72 ALS/FTD. Based on our findings, the exosome complex represents a promising cellular pathway that yields the potential of novel therapeutic strategies.