Antibodies Against Key ALS Protein Reveal New Disease Insights

Patrícia Silva, PhD avatar

by Patrícia Silva, PhD |

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amyotrophic lateral sclerosis therapy

Researchers at the University of Toronto and the Sunnybrook Health Sciences Centre in Canada recently reported the development of two new antibodies against a protein that plays a key role in amyotrophic lateral sclerosis (ALS) – C9ORF72. The study was published in the journal Annals of Neurology and is entitled “Isoform Specific Antibodies Reveal Distinct Subcellular Localizations of C9orf72 in Amyotrophic Lateral Sclerosis”.

ALS is a progressive neurodegenerative disease characterized by the gradual degeneration and atrophy of motor neurons in the brain and spinal cord that are responsible for controlling essential voluntary muscles, such as the ones related to movement, speaking, eating, and even breathing. ALS patients may become totally paralyzed and the majority dies due to respiratory failure within two to five years after diagnosis. It is estimated that more than 300,000 Americans suffer from the disease and there is currently no cure or life-prolonging treatments.

It is known that the major genetic cause of ALS is a repeat expansion in the gene C9ORF72 that leads to a decrease in protein expression. In order to study the role of the C9ORF72 protein, researchers have employed antibodies against the protein; however, the ones currently available perform poorly, with a reduced specificity and sensitivity, and not able to distinguish between the two natural isoforms of the protein (54 and 24 kilodalton isoforms).

Now, researchers developed two new C9ORF72 antibodies that allow the discrimination of the two protein isoforms and therefore their individual study. The team reported that in spinal motor neurons from neurologically healthy individuals, the short C9ORF72 protein isoform (24 kilodalton) localizes to the nuclear membrane of neurons, whereas the long isoform (54 kilodalton) is found in the cytoplasm. However, in ALS patients, the short C9ORF72 protein isoform was mainly localized in the plasma membrane, while the long isoform remained in the cytoplasm.

The team suggests that the short C9ORF72 protein isoform might participate in nuclear import, as it was found to co-localize with two specific proteins that regulate the trafficking of proteins into the nucleus.

Interestingly, researchers also reported that the short C9ORF72 protein isoform might guide another protein linked to ALS into the nucleus, the TDP-43. The TDP-43 protein is usually found within the nucleus, although in diseased neurons it is often found in the cytoplasm. The accumulation of TDP-43 protein is a typical feature of ALS.

Based on the findings obtained with their new antibodies, researchers proposed a model in which C9ORF72 abnormalities could result in the absence of the short isoform in the nuclear membrane, blocking TDP-43 entrance into the nucleus. The authors believe that other factors besides the repeat expansion in C9ORF72 probably also contribute to C9ORF72 localization and subsequent TDP-43 import. More studies are however required to confirm this hypothesis.

As for the C9ORF72 antibodies developed by the team, “I think they are going to be a phenomenal resource,” commented Dr. Tania Gendron from the Mayo Clinic, who was not involved in the study, in a news release. “The antibodies look really clean,” The research team believes that their new antibodies might help elucidate the function of the C9ORF72 protein and its role on ALS.