TARDBP and neurodegenerative disease: In the adult-onset progressive neurodegenerative diseases, aging factors and internal stress stimuli originally arising from the C9ORF72 repeat-mediated toxicity (including DPR-induced oxidative stress24, stress granule dysfunction26, 28, altered ER homeostasis72, 73, and TDP-43 mis-localization11) may trigger a feedforward loop to upregulate RAN translation and generate an increasing amount of DPRs that exert more toxicity and eventually lead to neuronal dysfunction, degeneration, and ultimately death, thereby driving relentless disease progression (Fig. 6g).