Figure 1.

Proposed model of FUS-mediated neurodegeneration. FUS homeostasis is essential for maintaining both protein and RNA homeostasis. FUS protein binds directly to FUS mRNA. The FUS level is possibly maintained through nonsense-mediated decay and/or miRNA-mediated mechanisms. An elevated FUS level produces both gain-of-toxicity properties (by either increasing proteotoxic stress through autophagy inhibition or expression of stress genes), and loss of RNA-processing function affecting genes involved with long transcripts and synaptic regulation. Together these changes cause neuronal and synaptic dysfunction and eventual neuronal death.