Perturbed Transport into Cellular Nucleus Linked to ALS

Three recent studies published in the journals Nature and Nature Neuroscience identified a mutation in some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) that leads to neuronal death by disrupting the movement of molecules within the cellular nucleus.

ALS and FTD are characterized by death of specific neurons leading to impaired movement and paralysis, in the case of ALS, and progressive problems with behavior, language and thinking in FTD. Previous research identified a specific mutation in the C9orf72 gene in inherited ALS (40 percent) and inherited FTD (25 percent) cases, and on non-inherited forms of both diseases of up to 10 percent.

The specific mutation in the C9orf72 gene leads to an increase of repeats in six specific nucleotides (DNA’s building blocks), resulting in the production of RNA molecules that interfere with the normal functioning of proteins in the cell. The RNA  also leads to the production of toxic proteins called dipeptide repeat proteins. What remained unknown, however, was how these specific mutations affected signaling pathways inside neurons.

In all three independent studies, scientists discovered that the mutation in the C9orf72 gene disrupts the transport across the nuclear membrane in neurons derived from patients’ skin cells. One team led by J. Paul Taylor, MD, PhD, a researcher at St. Jude’s Children’s Research Hospital in Memphis, Tennessee, found that in affected neurons, the RNA content inside the cells’ nucleus was significantly higher, therefore suggesting an imbalanced transport when compared to neurons derived from healthy cells. The other two teams discovered that proteins from patient-derived neurons were also accumulating inside the nucleus. Dr. Taylor’s study can be found here.

Amelie Gubitz, PhD, program director at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) commented, “This research shines a spotlight on the role of nuclear transport in the health of neurons. The results provide new insights into how this mutation derails an essential process in neurons and opens new avenues for therapy development.”

Another team led by Jeffrey Rothstein, MD, PhD, from Johns Hopkins University in Baltimore, Maryland, focused on the abnormal RNA produced as a consequence of the C9orf72 mutation, observing it affected a key player in the transport of molecules into the nucleus, a protein called RanGAP. By preventing the mutated RNA from interacting with RanGAP using chemical compounds, the team resolved the transport defect and re-established the flow of proteins into the nucleus. Moreover, when increasing the production of RanGAP protein, there was less neuronal death and consequently a reduction in motor problems caused by the mutation.

Dr. Rothstein noted, “This research defines the tipping point for how both ALS and FTD start, which is the interruption of nuclear-cytoplasmic transport. By examining a combination of fly models, living human brain cells, and real human tissue from autopsies, these studies comprehensively teach us what starts the disease.” Dr. Rothstein’s study can be found here.

The third team of scientists, led by Stanford University’s Aaron Gitler, PhD, investigated the role of toxic dipeptide repeat proteins produced by the C9orf72 mutation. They found that nuclear transport genes determined the harmful effects of these toxic proteins in the cell. Dr. Gitler stated, “It’s encouraging that multiple groups, using independent approaches, have all converged on the same genes and pathways.” Dr. Gitler’s study can be found here.

Overall, the three studies suggest that increasing and facilitating the transport of molecules into the nucleus could become a potential therapeutic strategy for treating some forms of ALS and FTD.