Overexpression of nuclear FUS induces neuronal cell death

- The pathogenesis of FUS-related ALS and FTLD is not clearly determined.
- FUS may exhibit neuronal toxicity in both gain-of-function and loss-of-function manners.
- The low-level overexpression of FUS, but not knocking-down of FUS, induced neuronal cell death.
- Nuclear FUS, but not cytoplasmic FUS, induced neuronal cell death.
- The gain-of-function of FUS in the nucleus contributes to the pathogenesis of FUS-linked neurodegenerative diseases.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative diseases that overlap clinically, genetically, and pathologically. Dysregulation of fused in sarcoma (FUS) has been hypothesized to cause ALS and FTLD in gain-of-function and/or loss-of-function manners. However, the link between the pathogenesis of ALS/FTLD and dysfunction of FUS has not been clearly determined. In this study, we found that overexpression of FUS, but not knocking-down of endogenous FUS expression, induces death in motor neuronal NSC34 cells and primary cortical neurons via the mitochondrial apoptotic pathway, possibly independently of transactive response DNA-binding protein-43. Furthermore, we found that nuclear FUS, but not cytoplasmic FUS, is responsible for FUS-induced neuronal cell death. These observations suggest that the gain-of-function of FUS in the nucleus contributes to the pathogenesis of FUS-linked neurodegenerative diseases.

118