Effects of ALS-associated mutations on the in vivo aggregation and toxicity of human FUS/TLS protein

Multiple mutations in two genes encoding proteins involved in the intracellular RNA metabolism, maturation and transport, transactive response (TAR)-DNA-binding protein 43 (TDP-43) and fused in sarcoma/translated in liposarcoma (FUS/TLS), have been associated with the development of familiar and sporadic forms ALS and FTLD-U. Moreover, both TDP-43 and FUS/TLS or their truncated forms were identified as major constituents of characteristic intracellular inclusions in the neuronal and glial cells of patients with familiar and sporadic forms of ALS and FTLD-U. However, neither the mechanism of these proteins aggregation nor the consequences of inclusion formation to brain cell physiology is known. To study the effect of FUS/TLS mutations associated with human neurodegenerative disorders on aggregation and toxicity of this protein in vivo we employed a cellular model system, SH-SY5Y human neuroblastoma cell lines expressing wild type or various mutated and truncated forms of FUS/TLS as eGFP fusion proteins.