Unraveling molecular biology of C9ORF72 repeat expansions in amyotrophic lateral sclerosis-frontotemporal dementia: Implications for therapy

Abstract Hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (c9ORF72) is the leading cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9-ALS/FTD). Most of the evidence from neuropathological studies and animal and cellular models supports that toxicity from repeat-expanded RNA transcripts and encoded dipeptide repeat proteins are more important contributors to disease pathogenesis than loss of the C9ORF72 protein function. Recent evidence supports that both loss of the function and gain of toxicity may be converging synergistically. Several biological pathways including nucleocytoplasmic transport, stress granule assembly, nucleolar function, protein translation, and DNA stability are aberrantly affected, but it is not determined which pathways lead to neurodegeneration disease and which are consequences. The multiplicity of disease mechanisms and pathways has generated a number of potential therapeutic targets and approaches and biomarkers that are now beginning to be tested in clinical trials, a testament to the rapid progress that has been made in unraveling the neurobiology of c9-ALS/FTD.