Interaction of amyotrophic lateral sclerosis/frontotemporal lobar degeneration–associated fused-in-sarcoma with proteins involved in metabolic and protein degradation pathways

Fused-in-sarcoma (FUS) is a nuclear protein linked to amyotrophic lateral sclerosis and frontotemporal dementia. Under pathologic conditions, FUS frequently is accumulated in cytosoplasm, but how this altered distribution affects the protein interaction pattern of FUS is unclear. Using dual-tag affinity purification and mass spectrometry, we compared the interactome of the wild-type FUS and the P525 L mutant, which causes juvenile amyotrophic lateral sclerosis with the most severe phenotypes. The mutant FUS retained the ability to bind proteins involved in RNA metabolism. We found significant increased binding of P525 L to many metabolic enzymes. Furthermore, we identified and confirmed some novel interactions between FUS and proteins involved in neurodegenerative diseases and/or ubiquitin proteasome pathway, such as VCP/p97, PSF, UBA 1, and 26S proteosome non-ATPase regulatory subunit 12 (PSMD12/Rpn5). Accordingly, we have observed significantly reduced ATP levels and increased accumulation of poly-ubiquitinated proteins in cells with FUS accumulation. Therefore, our study suggested new mechanisms whereby FUS accumulation leads to defective energy metabolism and protein degradation by directly interacting with key regulators in these pathways.