FUS, TDP-43 Combined Activity Disrupted in ALS, Dementia

Study in Drosophila ID's common genetic pathway disrupted in ALS, frontotemporal dementia

WEDNESDAY, Sept. 14 (HealthDay News) -- The RNA/DNA-binding proteins fused in sarcoma (FUS, also known as TLS) and TAR DNA binding protein-43 (TDP-43) function together in vivo in a common genetic pathway in neurons, and mutations in either protein may disrupt the combined activities of both of these proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), according to an experimental study published online Sept. 1 in the Journal of Clinical Investigation.

Ji-Wu Wang, Ph.D., from the Columbia University Medical Center in New York City, and colleagues examined whether FUS and TDP-43 functioned together in a shared molecular genetic pathway critical for long-term survival of specific neuronal subtypes in Drosophila to evaluate if mutations in either protein disrupted these processes. Drosophila mutants in which the FUS/TLS and TDP-43 homologs were disrupted, were examined. The interaction between the two genes was determined by cross-rescuing FUS/TLS or TDP-43 mutants.

The investigators found that, compared to normal flies, those with mutant FUS have decreased adult viability, diminished locomotor speed, and reduced life-span. The mutant flies were rescued by inserting wild-type human FUS into their genome, but not with ALS mutant human FUS. Flies with mutant TDP-43 showed similar but more severe deficits. Cross-rescue analysis revealed that FUS acts together with and downstream of TDP-43 in a common genetic pathway in neurons. These proteins associated with each other in an RNA-dependent complex.

"Our results establish that FUS and TDP-43 function together in vivo and suggest that molecular pathways requiring the combined activities of both of these proteins may be disrupted in ALS and FTD," the authors write.

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