The hundreds or thousands of GGGGCC nucleotide repeat expansion in the intron of C9orf72 gene drives the pathogenesis of ALS through the loss of the normal function and the toxic effects acquisition of C9orf72, the RNA amplification, the dipeptide repeat proteins aggregation and the C9orf72 haploid dysfunction, which produces the cytotoxic to interfere and affect the protein degradation via impairing UPS, producing the ubiquitin-positive characteristic pathological neuronal inclusions. Here, C9orf72 is linked to amyotrophic lateral sclerosis.