Two New Studies Identify Disrupted Trafficking Inside Neurons as the Cause for Known ALS Mutation

Two new studies, one entitled “GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport” and another “The C9orf72 repeat expansion disrupts nucleocytoplasmic transport”, report the discovery of a key mechanism underlying amyotrophic lateral sclerosis’ onset which is associated with C9orf72 mutation (the most common genetic defect associated with amyotrophic lateral sclerosis). The research team found that ALS-associated C9orf72 mutation pathogenesis is due to deviations in the normal transport of molecules across the nucleus. Both studies were published in the journal Nature.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease characterized by degeneration of nerve cells over time. ALS patients gradually loose the ability to control muscle movement and succumb to total paralysis within two to five years after diagnosis.

In the first study, scientists at the Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St Jude Children’s Research Hospital discovered that the defective C9orf72 gene, located on human chromosome 9, leads to problems in the transport of RNA molecules from cells’ nuclei. This causes RNA molecules to accumulate inside the nucleus, a feature also observed in ALS patients with the mutation. The team performed several studies using cells from fruit flies carrying the genetic defect (a model organism for human diseases) and found 18 genes which are differently expressed, either worsening or mitigating the effects of the gene mutation. All the 18 genes identified coded for proteins involved in the transport of molecules (RNA and proteins) in and out of the nucleus, or components of the nuclear “gates” regulating this traffic, called nuclear pores. This study was supported by the ALS Association’s Greater Chicago Chapter State of Illinois Grant.

Paul Taylor, M.D., Ph.D., of St. Jude’s and study lead author commented, “C9ORF72 mutations are by far the most common genetic defect associated with both ALS and FTD, so understanding how the mutation causes disease is tremendously important for efforts to develop therapies to stop or reverse the death of neurons in the brain and spinal cord of patients.”

In the second study, researchers at the Johns Hopkins University identified that the protein RanGAP (in fruit fly and equivalent to the human protein RanGAP1) interacts with the expanded RNA molecule of the C9orf72 mutation. RanGAP1 regulates the nuclear traffic inside cells, including the motor neurons associated with ALS. The team discovered that this interaction disrupted RanGAP’s normal function (aiding in the transport of molecules through nuclear pores). Instead, both in fly and human brain cells from patients with the ALS-associated C9orf72 mutation, RanGAP aggregated outside the nucleus inhibiting the transport of proteins that depend on RanGAP. Targeting the extra RNA molecule resulting from the C9orf72 mutation was an effective therapeutic.

Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The ALS Association noted, “These exciting results focus our attention more strongly on the role of cross-membrane trafficking in understanding how the C9orf72 gene causes ALS. “The ability of experimental treatments to reverse these effects in this model also gives us more reason to hope that a similar approach may offer benefits in people with ALS. This study and the recent report by a second group also showing defects in nuclear transport provide a stronger basis for developing therapy to target this important pathway.”