C9orf72
C9orf72 is the most common known genetic cause of both ALS and FTD, and it is the gene that firmly established these conditions as a disease spectrum. It is inherited in an autosomal dominant pattern and accounts for a majority of familial ALS and FTD cases.
Normal function
The normal function of C9orf72 is not fully understood, but it appears to play roles in vesicle trafficking (how molecules are sent between compartments of the cell), autophagy, and immune regulation. It may help regulate membrane dynamics and cellular cleanup systems, placing it at the intersection of proteostasis and immune signaling.
Mutation and effect
Disease is caused by a hexanucleotide repeat expansion (GGGGCC) in a noncoding (does not make a protein) region of C9orf72. Downstream, this leads to TDP-43 moving from the nucleus into the cell body, where it is unable to aid in RNA processing. All in all these cause three main problems: toxic RNA species, production of abnormal proteins, and reduced normal C9orf72 function.
Implications for treatment
C9orf72 disease presents with overlapping ALS and FTD features. Compared to non-genetic disease, it may show more behavioral symptoms, psychiatric features, and earlier cognitive involvement, along with TDP-43 pathology. C9orf72 is a major target for antisense oligonucleotide (ASO) therapies aimed at reducing toxic RNA and abnormal protein production. This is one of the most advanced gene-targeted strategies in the ALS field.
Research focus
Research on C9orf72 is focused on determining which part of the mutation is most responsible for disease: loss of normal C9orf72 function, toxic RNA accumulation, production of abnormal dipeptide repeat proteins, or some combination of all three. This question matters because each mechanism points toward a different treatment strategy. Another major research focus is understanding why the same C9orf72 expansion can produce different clinical outcomes. Some individuals develop ALS, others develop FTD, and some develop both. Researchers are studying genetic modifiers, repeat length, immune signaling, nucleocytoplasmic transport, and cell-type vulnerability to explain this variation.
Sources
Renton, A. E., Majounie, E., Waite, A., et al. (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.
Balendra, R., & Isaacs, A. M. (2018). C9orf72-mediated ALS and FTD: multiple pathways to disease.
Smeyers, J., Banchi, E.-G., & Latouche, M. (2021). C9ORF72: What it is, what it does, and why it matters.
Smeele, P. H., et al. (2024). ALS’ perfect storm: C9orf72-associated toxic dipeptide repeat proteins and impaired protein homeostasis.