ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function

TLDR

Mutations in the RNA‑binding protein FUS cause aggressive juvenile ALS, yet whether motor neuron loss arises from loss‑of‑function or toxic gain‑of‑function mechanisms remains unresolved. The study aimed to characterize transgenic FUS mouse lines to investigate the mechanisms underlying mutant‑dependent motor neuron degeneration. Using these lines, the authors observed progressive, mutant‑dependent motor neuron loss preceded by early neuromuscular junction abnormalities, and showed that conditional postnatal deletion of FUS does not affect motor neuron survival or function. The results demonstrate that motor neuron degeneration in ALS is driven by toxic gain‑of‑function properties of mutant FUS rather than loss of endogenous FUS activity.

Abstract

Abstract Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.