FUScinating insights into motor neuron degeneration

Abstract

Point mutations in FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease—but do they do that by a loss of the protein's normal function, or by endowing it with novel toxic functions, or both? In this issue of The EMBO Journal, Scekic‐Zahirovic et al (2016) report that mutant FUS, but not the complete loss of FUS, triggers motor neuron degeneration in mice, arguing for a toxic gain‐of‐function mechanism.

Figure 1. Cytosolic mislocalization of FUS, but not loss of FUS, is toxic to motor neurons

FUS is a ubiquitously expressed DNA/RNA‐binding protein that is normally localized in the nucleus, where it regulates RNA expression and splicing. FUS knockout mice (Fus ^−/−) show loss‐of‐function (LOF) gene expression changes and die postnatally, but have normal motor neurons. Mice with a targeted deletion of the nuclear localization signal (Fus ^ΔNLS/ΔNLS) have FUS in the cytosol rather than in the nucleus. This causes a nuclear LOF and postnatal death, but also gain‐of‐function (GOF) changes that lead to motor neuron degeneration. Motor neuron apoptosis can be rescued by motor neuron‐specific reversal of the NLS deletion (ChAT‐Cre Fus ^ΔNLS/ΔNLS), demonstrating that cytosolic FUS triggers cell‐autonomous motor neuron loss.