- The gene for FUS was associated in 2009 with ALS, and recent studies suggest that abnormal FUS protein may play a role in at least some cases of both inherited and noninherited forms of the disease.
- ALS-linked mutations in FUS affect the protein's function and lead to cellular toxicity in, and death of, nerve cells.
- Understanding the functions of normal and mutated forms of FUS protein is expected to shed light on the vulnerability of motor neurons to degeneration in ALS.
- Read comments from the experts in Figuring Out FUS.
In 2009, it was discovered that genetic mutations in the fused in sarcoma gene — FUS for short — were linked to some cases of ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).
|Left — FUS protein (green) is shown in yeast cells. Right — Aggregates of purified FUS protein resemble the FUS aggregates found in degenerating motor neurons of people with ALS.
Subsequent studies of the FUS protein have stirred the ALS research pot and raised the idea that disruptions in RNA metabolism may be a crucial part of what’s going awry in the disease.
Mutated FUS is now thought to be the primary cause of 4 to 5 percent of familial (inherited) ALS cases. In addition, abnormal clumps containing FUS protein have been found in the motor neurons of people with the more common sporadic (noninherited) form of ALS, suggesting a critical role for FUS in the ALS disease process.
Evidence suggests that the only cases of ALS in which FUS doesn’t appear in such protein clumps are familial cases caused by mutations in the SOD1 gene.
Understanding FUS — what it does, and what happens when it functions abnormally — should provide a clearer understanding of the ALS disease process in both the inherited and noninherited forms of the disease.
Mutations cause FUS to gather in the wrong place
FUS normally resides inside the cell nucleus, where it primarily functions as an RNA binding protein. (RNA is the chemical step between DNA and protein synthesis. RNA binding proteins are involved in RNA processing, which is required to prepare it to be efficiently decoded by the cell’s protein-building machinery.)
Studies in cell cultures have shown that ALS-linked mutations in the FUS gene disrupt the nuclear localization signal (NLS), the molecular mechanism that makes sure the FUS protein goes to the cell nucleus.
Without the NLS to guide it, FUS protein improperly locates outside the nucleus in the compartment of the cell called the cytoplasm.
Once in the cytoplasm, FUS recruits other proteins essential for RNA processing into the area, resulting in protein clumps called inclusion bodies or aggregates. These clumps have been observed in ALS-affected motor neurons, and in the glial cells that nourish and support them.
FUS connected to cellular toxicity in ALS
In addition to mislocating to the cytoplasm, FUS protein also causes cellular toxicity and cell death in the ALS disease process.
In yeast models, a direct relationship between toxicity and protein levels exists. The higher the levels of mutant FUS protein (or higher-than-average levels of normal FUS protein) the more damaging the toxic effects on the cell.
Research scientists have identified five yeast proteins that suppress toxic human FUS in yeast models. Interestingly, the proteins did this without affecting FUS protein levels, location of FUS in the cell, or FUS-containing aggregates in the cytoplasm.
Additionally, a human version of one of the five toxicity-fighting yeast proteins has been found to reduce toxicity in the yeast model. The human protein, hUPF1, may be a potential target in development of therapies that take aim at FUS-related ALS.
FUS and TDP43: Alike but different
Like FUS, mutated TDP43 also has been identified as a primary cause of some cases of ALS. The two proteins bear a number of common features, beginning with their similar structure.
Both the FUS and TDP43 genes carry coded instructions for RNA-binding proteins which, in ALS, mislocate from the cell nucleus to the cytoplasm, where they form aggregates.
However, the two differ in the ways in which they cause damage to cells. Requirements for FUS and TDP43 aggregation are different, as are the specific ways in which the two proteins affect cells at later stages. While mutations in the FUS gene primarily alter the protein’s location, TDP43 mutations mainly affect the protein’s aggregation and toxicity characteristics.
Screens designed to identify genes that affect the toxicity associated with FUS and TDP43 found two very different sets of modulators.
Only two genes have been identified that are able to modulate the toxicities of both FUS and TDP43, suggesting that while the two proteins cause cell death via different pathways, these pathways may share some common elements.
Studies conducted in a recently developed fruit fly research model have shown that interaction of normal FUS with mutated TDP43 enhances motor neuron death; and likewise, interaction of normal TDP43 with mutated FUS enhances neurodegeneration. This synergistic interaction suggests the two proteins’ pathways do intersect at some point (likely further downstream) in the toxicity process.