Repetitive DNA tracts (microsatellites) occur thousands of times throughout the human genome, and their expansion is known to cause many diseases. Expansion of CAG repeats encoding polyglutamine (polyQ) tracts is a pathological cause of nine neurodegenerative diseases: spinal and bulbar muscular atrophy, Huntington’s disease, dentatorubropallidoluysian atrophy, and six autosomal dominant forms of spinocerebellar ataxia (SCA1, 2, 3, 6, 7, and 17) [1]. In 2011, two independent groups found an intronic GGGGCC (G4C2) expansion mutant in C9orf12 as the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [2, 3]. Evidence from these studies supports the idea that both loss-of-function and gain-of-function mechanisms contribute to these diseases. Bidirectional transcription of mutant C9orf72 produces sense and antisense hexanucleotide repeat expansions. These RNA tracts can undergo repeat-associated non-AUG translation to produce aggregated dipeptides. The aggregated substances can lead to nuclear dysfunction, affecting RNA splicing and transcription as well as causing DNA damage. Proteostasis pathways have also been implicated in disease pathology, including impairments in autophagy and lysosomal function, the unfolded protein response, and the endoplasmic reticulum [4], as well as the ubiquitin–proteasome system [5]. Besides gain-of-function mechanisms, the G4C2 repeats (G4C2r) also interfere with the expression of the C9orf72 gene product, leading to a decreased protein level. Therefore, both C9orf72 deficiency and toxic gain-of-function mechanisms can lead to various disruptions of nucleotides and proteins, although the pathological mechanisms remain largely unclear (Fig. 1).