Details

Autor(en) / Beteiligte

• Sharma, Aarti
• Lyashchenko, Alexander K.
• Lu, Lei
• Nasrabady, Sara Ebrahimi
• Elmaleh, Margot
• Mendelsohn, Monica
• Nemes, Adriana
• Tapia, Juan Carlos
• Mentis, George Z.
• Shneider, Neil A.

Titel

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

Ist Teil von

• Nature communications, 2016-02, Vol.7 (1), p.10465-14, Article 10465

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. The mechanism by which FUS mutations cause familial ALS remains unclear. Here, the authors use mouse transgenic models to show that a toxic gain-of-function underlies motor neuron degeneration, and that the toxicity of mutant FUS does not depend on a loss or excess of FUS activity.