Packard Center investigator Edor Kabashi’s recent work into the C9orf72 gene is featured in a new study in the Annals of Neurology.
Since Packard scientists helped discover the C9orf72 repeat expansion in 2011, the most common genetic cause of familial ALS and frontotemporal dementia (FTD), researchers have been trying to figure out how this mutation led to ALS. In a new study published in the Annals of Neurology, Packard scientist Edor Kabashi and a team of French scientists have found at least one way through which the C9orf72 mutation causes disease.
In brain samples and lymphoblast cell lines obtained from several ALS/FTD patients carrying the C9orf72 repeat expansion, Kabashi and colleagues showed that levels of C9orf72 mRNA were significantly lower than control individuals. Since all vertebrates, including zebrafish, carry a similar version (orthologue) of the C9orf72 gene, Kabashi and colleagues blocked C9orf72 mRNA translation in zebrafish embryos. This C9orf72 knockdown led to significant abnormalities in axonal projections of motor neurons, deficits in spontaneous swimming as well as in performing a tactile escape response in zebrafish larvae. The cellular and behavioral-related phenotypes were reversed when Kabashi and colleagues modified the zebrafish genome to overexpress the human C9orf72 gene. The researchers concluded that these results provide strong evidence that loss of normal C9orf72 function caused by the repeat expansion is a key factor in the development of ALS/FTD in these patients.