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

Aarti Sharma, Alexander K. Lyashchenko, Lei Lu, Sara Ebrahimi Nasrabady, Margot Elmaleh, Monica Mendelsohn, Adriana Nemes, Juan Carlos Tapia, George Z. Mentis and Neil A. Shneider ()
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Aarti Sharma: Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423
Alexander K. Lyashchenko: Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423
Lei Lu: Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423
Sara Ebrahimi Nasrabady: Center for Motor Neuron Biology and Disease, Columbia University
Margot Elmaleh: Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423
Monica Mendelsohn: Center for Motor Neuron Biology and Disease, Columbia University
Adriana Nemes: Howard Hughes Medical Institute, Columbia University
Juan Carlos Tapia: Columbia University
George Z. Mentis: Center for Motor Neuron Biology and Disease, Columbia University
Neil A. Shneider: Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423

Nature Communications, 2016, vol. 7, issue 1, 1-14

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.

Date: 2016
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DOI: 10.1038/ncomms10465

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