As neurologists and neurobiologists gathered for the Third International Research Workshop on Frontotemporal Dementia in ALS, 21-25 June in London, Ontario, Canada, the big buzz was all about Fused in Sarcoma (FUS), the gene recently discovered to be mutated in 3 to 5 percent of people with inherited amyotrophic lateral sclerosis. Christopher Shaw of King’s College London described how, after a 10-year effort in collaboration with Robert Brown of the University of Massachusetts in Worcester, researchers plucked the FUS gene from a set of families with inherited ALS (see ARF related news story; Kwiatkowski et al., 2009 and Vance et al., 2009). The primarily nuclear protein is involved in transcribing, splicing, and transporting RNA; it is not yet clear what links these functions to motor neuron disease. Scientists have found more than a dozen mutations, mostly in the carboxyl-terminal region of the protein, which cause it to form inclusions in cultured cells as well as in human spinal cord. It has been just four months since that work was published, but others have already tackled FUS in their own studies.
Some people with ALS also get FTD, and the two conditions are linked by the pathologic protein TDP-43. Ian Mackenzie of the University of British Columbia in Vancouver presented new data on FUS pathology in frontotemporal dementia. FTD cases fall into two main categories: those with tau pathology, and those with TDP-43 pathology. But a small subset of cases fit neither category, with ubiquitin-positive inclusions that lack both tau and TDP-43 (Mackenzie et al., 2008 and Roeber et al., 2008).
This atypical FTD has disease onset between 28 and 55 years of age and a quickly progressing condition that lasts between four and 15 years. The disease includes severe personality and behavioral changes, sometimes leading to antisocial or even criminal activity. It does not appear to be inherited.
Mackenzie and colleagues analyzed brain tissue from 15 people who had this atypical FTD and discovered very unusual neuronal inclusions, he said. In addition to round or crescent-shaped cytoplasmic inclusions, the scientists observed twisted, thick filaments inside the nucleus.
When they immunostained their atypical FTD samples for FUS, the normal pattern—strong signal in the nucleus, and some in the cytoplasm—was still apparent. However, there was additional staining for both the cytoplasmic and intranuclear inclusions. Inclusions did not stain positive for FUS in samples from people with FTD associated with tau or TDP-43. The scientists found no mutations in the FUS sequence of several people with atypical FTD. Mackenzie and colleagues discovered similar FUS pathology in samples from people with basophilic inclusion body disease and neuronal intermediate filament inclusion disease, which also cause frontotemporal dementia. These FUSopathies form a new molecular class of FTD, Mackenzie said, although it is not yet clear whether all are the same disease, or different conditions with similar pathology.
Some of the answers about FUS are likely to come from animal models, and at least a few are already in the works. Don Cleveland of the University of California, San Diego, reported on mouse models he is developing in collaboration with Shaw. He has mice expressing wild-type as well as mutant human FUS at varying levels, under control of the native or prion promoter, which drives expression in the nervous system. He noted that in animals that express high levels of the human transgene, it appears to dampen expression of mouse FUS, with less mouse protein present. In the nervous system, the protein is primarily nuclear, with a bit of cytoplasmic expression. In the case of mutant FUS, some protein formed aggregates in the spinal cord. Now, Cleveland said, it’s a waiting game. Some lines are only three months old, and he and his colleagues must be patient as they hope for a phenotype.
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