Novel antibodies highlight new cellular link in the development of amyotrophic lateral sclerosis

Written by Alice Weatherston

The discovery that mutations in the gene termed C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) in 2011 was a major breakthrough in the understanding of a disease that currently has no effective treatment options. Now, researchers from the University of Toronto (ON, Canada) have taken this research a step further and identified the key role of C9orf72 within diseased ALS neurons, using newly developed antibodies. The findings were published recently in Annals of Neurology.
Janice Robertson and her team at the Tanz Centre for Research in Neurodegenerative Diseases (University of Toronto) were able to develop novel antibodies capable of specifically detecting C9orf72 within human tissues as well as distinguishing between the long and short isoforms of the gene.

Through the use of these antibodies, the team revealed that C9orf72 is localized to the nuclear membrane in healthy neurons, but that within diseased neurons it is mislocalized to the outer plasma membrane.

In addition to this, the team also discovered that C9orf72 can directly interact with components of the nuclear shuttling complex, meaning gene mutations can cause disruption to the transport of proteins across the nuclear membrane. Importantly, one such protein which was affected was TDP-43, a protein of which accumulation in the cytoplasm is often the cause of diagnosis of ALS. The team identified that the loss of C9orf72 from the nuclear membrane correlated with TDP-43 pathology, a vital link that had not previously been identified.

“The possible involvement of C9orf72 in the shuttling between nucleus and cytoplasm opens intriguing new avenues of research into the causes of ALS – and hopefully, one day an effective treatment or cure,” commentd Robertson.

The team are now distributing their antibodies to other ALS research labs so that further research can be carried out on C9orf72’s role in the development of ALS worldwide.

Source: University of Toronto press release