On the one hand, RNA foci and DPRs seem to cause neurodegeneration and often lead to motor neuron disease when overexpressed (Chew et al., 2015; Zhang et al., 2016; Herranz-Martin et al., 2017; Schludi et al., 2017; Choi et al., 2019; Hao et al., 2019; LaClair et al., 2020), whereas most BAC models presenting RNA foci and RAN proteins at physiological levels do not fully develop neurodegeneration or FTD/ALS behavioral phenotypes (O’Rourke et al., 2015; Peters et al., 2015; Jiang et al., 2016; Liu et al., 2016; Mordes et al., 2020; Nguyen et al., 2020). The gene discussed is RAN; the disease is amyotrophic lateral sclerosis.