C9orf72 and amyotrophic lateral sclerosis: Loss of SMCR8 leads to a similar phenotype as C9ORF72 depletion and results in defective autophagy, indicating that this interaction is required for modulating autophagy induction [242].Whereas a recent study shows a new topic that depletion of C9ORF72 is not deleterious by itself but synergizes with Ataxin-2 toxicity to impair motor neuron's function and lead to neuronal cell death, thus revealing a double-hit pathological mechanism in ALS [237].