Carolinas Medical Center
Brooks, director of the MDA/ALS Center at Carolinas Medical Center, and colleagues are interested in the normal and abnormal molecular interactions of FUS, as well as microRNA regulation of FUS and effects on neurotoxicity in cells under stress.
“We find it interesting that proteins with similar functions are involved in the selective loss of motor neurons,” Brooks said, adding that the “million-dollar question” would be, “what molecular mechanisms could be targeted to prevent this selective loss,” and at what stage of human development could mutations or susceptibilities be identified?
Brooks noted that “unknown genes involved in FUS-related pathways may potentially represent drug targets in ALS,” and that “mutated FUS forms may be used in model systems to identify such targets.”
It’s important to study FUS, Brooks said, because ALS is still poorly understood, so any causative mutation, along with its mechanisms and effects, is worth in-depth investigation in the search for treatments and cures.
Siddique, former co-director of the MDA/ALS Center at Northwestern and frequent MDA grantee, is interested in the relationship between FUS and sporadic ALS. With colleagues, he is developing induced pluripotent stem cell (iPSC) lines for use as a model in the identification of the molecular signature of FUS.
Siddique’s group was the first to report the presence of abnormal FUS in the spinal cords of people with sporadic ALS.
Studies of FUS are applicable to both inherited and noninherited forms of ALS, “at least at the pathological level,” said Siddique.
He noted that the normal function of FUS (and, likewise, TDP43) is not known beyond its RNA-binding function. “We know very little about FUS; a lot is still left to learn,” Siddique said, adding that FUS is sometimes associated with cases of ALS in very young people, and — similar to TDP43 — also can cause dementia.
FUS is responsible for about 5 percent of familial ALS, or less than 1 percent of all ALS, Siddique said. Understanding its role “is important in large families, very early onset patients, and in uncovering its downstream or post-translational role in sporadic cases of the disease.”
University of Pennsylvania
Gitler and colleagues are investigating factors that contribute to FUS aggregation, and also what defines the cellular pathways that are affected when the protein is mislocalized in ALS.
“FUS is now the second RNA-binding protein linked to ALS,” Gitler said. “Since both FUS and TDP43 are very similar proteins, it has been widely assumed that they will contribute to disease by similar mechanisms. However, this hypothesis has not yet been tested.”
Gitler’s team is working to determine the similarities and differences between TDP43 and FUS, and the mechanisms by which they contribute to disease.
Emerging evidence indicates that in addition to mutated FUS contributing to inherited forms of ALS, normal FUS also can contribute to some sporadic cases of other neurodegenerative diseases, Gitler said. The extent to which FUS contributes to sporadic ALS still is uncertain, he said.
The identification of both TDP43 and FUS as causes of ALS “has solidified a role for RNA metabolism” in the disease, Gitler said. (RNA metabolism amounts to the production, processing and degradation of the molecule.)
“Understanding how FUS affects RNA metabolic pathways, normally and in disease, will contribute to our knowledge of cellular pathways with importance to ALS,” noted Gitler.
Ultimately, “FUS and TDP43 are both aggregation-prone RNA binding proteins,” Gitler said, noting that it will be important when developing therapeutic approaches to determine whether loss of normal function or a toxic “gain of function” is at work.
“An understanding of the similarities and differences between TDP43 and FUS will help guide individual therapies targeting specifically TDP43 or FUS, or perhaps a combination therapy targeting both.”
Louisiana State University Health Sciences Center
Pandey and colleagues are interested in understanding the normal functions of FUS and how ALS-linked mutations perturb the cellular function of the protein.
"We are also trying to determine the molecular targets and pathways that are altered due to disease-causing mutations in FUS, and we're interested in identifying genes that can influence onset and progression of the disease."
Pandey says the most interesting aspect of FUS in ALS is the mislocalization of the mutant protein from the nucleus to the cytoplasm — similar to what occurs with mutant TDP43.
"FUS is an interesting protein implicated in regulating multiple aspects of RNA function," Pandey says, "and we are interested in understanding the impact of mutated FUS on RNA processing."
Because mutations in FUS have been associated with both inherited and noninherited ALS, Pandey says, anything scientists learn about the protein may have implications for at least some cases in both forms of the disease.
Looking ahead to possible therapeutic strategies, Pandey notes, "Mutations in FUS were only identified in 2009 and we still don’t know the normal and abnormal functions of the protein." Still, progress is being made. "Although it has been only two years since the discovery of mutations in FUS, several labs have recently identified genes that modify the effects of mutant FUS toxicity."
J. Paul Taylor
St. Jude Children's Research Hospital
Taylor is interested in the normal function(s) of the FUS protein, and how the normal function is altered by disease-causing mutations.
One of the most interesting aspects of FUS, said Taylor is "the fact that TDP43 and FUS pathology seem to be mutually exclusive."
Taylor currently has support from MDA for research into the neurodegenerative disease spinal-bulbar muscular atrophy (SBMA).
Figuring out FUS "will illuminate the underlying role of altered RNA metabolism in ALS and related neurodegenerative diseases," Taylor said.
In fact, RNA binding proteins including FUS are the subject of Taylor's sixth Brain Research Conference, Nov. 10-11, 2011, in Washington, D.C.
University of Kentucky
Taylor noted that uncovering the mechanisms underlying normal and mutated FUS are of equal importance to another RNA binding protein, TDP43, as such details likely will be informative about sporadic ALS.
Kasarskis and colleagues are studying a group of extended family members with a FUS mutation called R521G.
The "FUS phenotype," or the way FUS-related ALS manifests, Kasarskis says, "is that of typical sporadic ALS," with signs and symptoms indicating that both upper and lower motor neurons are affected.
He notes that this is in contrast to many people affected by familial SOD1 ALS, who in his experience exhibit predominantly lower motor neuron signs.
Kasarskis says that understanding the functions of the FUS protein in normal motor neurons, as well as the mechanisms of the mutated protein in familial ALS will provide "important insights about the vulnerability of motor neurons to degeneration in ALS," and that the significance of FUS "will extend beyond the families affected by specific FUS mutations to a deeper understanding of motor neuron biology.
University of Pennsylvania
Shorter and colleagues are interested in defining the mechanisms by which FUS misfolds and how this misfolding might confer toxicity in motor neurons.
The aspect of FUS that Shorter finds most intriguing is the "prion-like domain" in its N-terminal (or front-end) region.
"We suspect that this domain is key to FUS misfolding and that FUS might even access conformations that are also accessed by prions," Shorter says, noting that he and colleauges "wonder if ALS pathology might be explained by a prion-like spread of FUS." He says it's important to understand how the misfolding of RNA-binding proteins like FUS and TDP43 are connected with ALS because an accurate understanding of this connection and how it might be corrupted will be an important aspect in developing therapeutic strategies.
Shorter notes that although FUS originally was connected with inherited forms of ALS, "evidence is now emerging that connects FUS to sporadic forms of the disease."
He says it's particularly important to elucidate FUS mechanisms and effects from those of TDP43, SOD1 and others, "because the mechanisms by which each protein confers neurodegeneration are likely to be different in many regards, but similar in others," and therefore, "it will be important to identify common strategies that target all forms of ALS, as well as specialized strategies specific to each form."
With regard to possible therapeutic strategies, Shorter says, "A key point here is that, at least in yeast, FUS toxicity can be countered without correcting FUS localization or reversing FUS aggregation. If this is also true in motor neurons, then therapies might not necessarily have to correct aggregation or localization. This is very encouraging, as reversing protein aggregation has been extremely difficult."
Musaro says that "although defined mutations have been linked to the ALS, a clear correlation between the genetic defect and the physiopathology of the disease has not yet been disclosed."
Musaro and colleagues are interested in defining the specific disease-causing roles of FUS and TDP43 on ALS disease. "The interesting aspect of FUS with regard to ALS pathology is its involvement in RNA metabolism," Musaro says.
Studies of FUS are applicable to both inherited and noninherited forms of the disease, Musaro says, "because mutations in the FUS gene have been shown to be responsible both in cases of familial and in cases of sporadic ALS. Thus, comparing FUS analyses in sporadic and familial cases of the disease will help uncover the molecular mechanisms involved.
"Figuring out the role of FUS in the disease process of both familial and sporadic forms of ALS will help to better understand its contributing role to ALS pathology," Musaro says."
The important thing to remember when it comes to comparing FUS mechanisms with those of TDP43, SOD1 and others, is that evidence is mounting that "ALS is a multisystemic and multifactorial disease. Therefore, research activity should focus on all of the genes involved in ALS; thus characterization of the disease-related effects of FUS, TDP43 and SOD1 [and others] should merit equal consideration."