Fly Model of ALS Suggested That Nuclear Localization of Mutant Protein Is Important for Toxicity

ALS Association-funded Haining Zhu, Ph.D., published together with Jianhang Jia, Ph.D., and colleagues in the publication Molecular Neurodegeneration demonstrating that over-expression of normal (Fused in Sarcoma) FUS protein and FUS protein carrying ALS-linked mutations led to motor degeneration and damage at the neuromuscular junction in a fly model.

Haining Zhu, Ph.D.

FUS is an RNA binding protein involved in many processes of RNA metabolism.  Mutations linked to about 4% of familial ALS cases have been identified.  How these mutations in FUS lead to ALS remains unclear.  The investigators used drosophila, a fly model, to understand the role of FUS in disease. Production of normal and mutant FUS induced progressive toxicity in multiple tissues in a dose and age-dependent manner.  Motor neurons degenerated through a cell death pathway called apoptosis.  The investigators demonstrated that nuclear localization of the mutant protein was required for the induced toxicity.

“The lack of toxicity in flies over expressing truncated FUS lacking the nuclear localization sequence (FUS-Δ32) and therefore deleting FUS from the nucleus was really striking,” said Dr. Zhu.  “It took us a while to re-do all experiments and double check everything to make sure it is right.  It appears that high levels of FUS inside the nucleus rather than the cytoplasmic inclusions caused toxicity in the transgenic flies.”

Jianhang Jia, Ph.D.

Dr. Zhu further said, “Although this study clarifies the location where toxicity is originated, the molecular mechanism of such toxicity remains unknown.  Additional studies are needed to further elucidate the molecular mechanism and to search for targets for ALS therapy development.”