About 1-3% of cases of familial ALS are due to mutations in profilin, a key regulator of actin dynamics (see July 2012 news; Wu et al., 2012; Smith et al., 2015). To determine how these changes in the axonal cytoskeleton could lead to the disease, researchers led by John Landers and Zuoshang Xu at the University of Massachusetts in Worcester created a mouse model of profilin-linked ALS (Yang et al., 2016). But despite extensive characterization of these mice, researchers remain unsure how mutations in profilin could contribute to the pathogenesis of the disease (see October 2016 news).
Now, Landers’ team reports that profilin may be critical to keep the muscle fibers and motor neurons connected by promoting the remodeling of neuromuscular junctions. The study found that the introduction of human profilin in Drosophila resulted in key changes in the architecture of larval neuromuscular junctions including elevated active zone density and an increased number of ghost boutons and filipodia. What’s more, these changes in morphology were either reduced or absent upon expression of either ALS-linked profilin C71G or M114T suggesting that a partial loss of function of profilin may underlie the disease.
The results add to growing evidence that reduced axonal actin dynamics may contribute to ALS including C9orf72 ALS, the most common form of the disease (see October 2016 news; Sivadasan et al., 2016).
The study is published on April 3 in Human Molecular Genetics.
The actin cytoskeleton is emerging as a critical player in the maintenance and function of neuromuscular junctions. To investigate the potential role of profilin at these structures, Lander’s team created Drosophila models of profilin-linked ALS. The models, created by expressing human wild-type or ALS-linked profilin C71G or M114T specifically in motor neurons, exhibit progressive motor deficits and reduced survival at the adult stage.
Now, Lander’s team is gearing up to perform genetic screens using these fly strains in hopes to identify proteins that interact with profilin at the NMJ. The approach may help reveal how profilin may promote the remodeling of neuromuscular junctions and thereby keep the muscle fibers and neurons connected. Stay tuned.
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Image on home page: Insect neuromuscular junction, M. Sulkowski, NICHD. CC BY 2.0 license.