Related Experiment Video
Updated: Mar 26, 2026
Real-Time Fluorescent Measurement of Synaptic Functions in Models of Amyotrophic Lateral Sclerosis
Published on: July 16, 2021
ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function
Aarti Sharma1, Alexander K Lyashchenko1, Lei Lu1
1Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423, New York, New York 10032, USA.
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.
Insights
Mutations in the FUS gene cause amyotrophic lateral sclerosis (ALS). This study shows that ALS is caused by toxic properties of mutant FUS, not loss of normal FUS function.
Area of Science:
- Neuroscience
- Genetics
Background:
- Mutations in the FUS gene are linked to amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease.
- The exact mechanisms by which mutant FUS leads to motor neuron degeneration remain unclear, with both loss-of-function and toxic gain-of-function hypotheses proposed.
Purpose of the Study:
- To investigate the pathogenic mechanisms of FUS mutations in ALS.
- To determine whether FUS loss-of-function or toxic gain-of-function is responsible for motor neuron degeneration in ALS.
Main Methods:
- Generation and characterization of transgenic FUS mouse models.
- Utilizing a conditional FUS knockout mutant to assess the role of endogenous FUS.
- Analysis of motor neuron survival, function, and neuromuscular junction integrity.
Main Results:
- Transgenic FUS mouse lines exhibited progressive, mutant-dependent motor neuron degeneration.
- Early structural and functional abnormalities were observed at the neuromuscular junction.
- Postnatal elimination of endogenous FUS did not affect motor neuron survival or function.
- Endogenous FUS did not contribute to the ALS phenotype induced by mutant FUS.
Conclusions:
- FUS-dependent motor neuron degeneration in ALS is caused by the acquisition of toxic properties by mutant FUS.
- These findings rule out a loss-of-function mechanism for FUS in ALS pathogenesis.
