Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1 transcription signature

Summary A G4C2 repeat expansion in the gene C9orf72 (C9) is the most common genetic cause of sporadic and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). What determines why cell death is triggered only in specific neuronal populations, while others remain ‘protected’ or are less susceptible to disease is still an open question. In particular, whether it is the transcriptional response to the accumulation of toxic insults or the initial cellular state that determines their vulnerability is still unknown. We have carried out a large-scale profiling of single cell transcriptional signatures throughout disease development in a Drosophila model of C9 repeat toxicity. This enabled us to monitor transcriptional shifts and track changes in cell populations during disease progression. We have identified neuronal populations which are depleted in response to C9 repeat expression, and therefore vulnerable to toxicity. On the other hand, other neuron types are resistant to toxicity, and maintain their cell number during disease progression. Our findings suggest that a major determinant of vulnerability is the transcriptional state of the cell before it is exposed to C9 repeat expression. We have identified a conserved transcriptional profile that is associated with resistance to C9 repeat toxicity. Neurons resistant to disease display a higher expression of genes involved in protein homeostasis, with Xbp1 identified as a crucial transcription factor determining neuronal vulnerability.