Profilin may act up at neuromuscular junctions in ALS

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).

A neuromuscular remodelista? The introduction of human profilin in Drosophila motor neurons in part, increased the number of filopodia and ghost boutons (arrows), immature synapses that contain synaptic vesicles but lack active zones. The results suggest that profilin may promote activity-dependent remodeling at these structures. (see Ataman et al., 2008). [Courtesy of Wu et al., 2017, Human Molecular Genetics.]

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, which involves the specific expression of human wild-type or ALS-linked profilin C71G or M114T in motor neurons, exhibits 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.

References

Wu CH, Giampetruzzi A, Tran H, Fallini C, Gao FB, Landers JE. A Drosophila model of ALS reveals a partial loss of function of causative human PFN1 mutants. Hum Mol Genet. 2017 Apr 3. [PubMed].

Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron DM, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz JA, Xu ZS, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meininger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH Jr, Landers JE. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012 Aug 23;488(7412):499-503. [PubMed].

Yang C, Danielson EW, Qiao T, Metterville J, Brown RH Jr, Landers JE, Xu Z. Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6209-E6218.  [PubMed].

Smith BN, Vance C, Scotter EL, Troakes C, Wong CH, Topp S, Maekawa S, King A, Mitchell JC, Lund K, Al-Chalabi A, Ticozzi N, Silani V, Sapp P, Brown RH Jr, Landers JE, Al-Sarraj S, Shaw CE. Novel mutations support a role for Profilin 1 in the pathogenesis of ALS. Neurobiol Aging. 2015 Mar;36(3):1602.e17-27. [PubMed].

Sivadasan R, Hornburg D, Drepper C, Frank N, Jablonka S, Hansel A, Lojewski X, Sterneckert J, Hermann A, Shaw PJ, Ince PG, Mann M, Meissner F, Sendtner M. C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons. Nat Neurosci. 2016 Dec;19(12):1610-1618. [PubMed].

Ataman B, Ashley J, Gorczyca M, Ramachandran P, Fouquet W, Sigrist SJ, Budnik V. Rapid activity-dependent modifications in synaptic structure and function require bidirectional Wnt signaling. Neuron. 2008 Mar 13;57(5):705-18. [PubMed].

Further Reading

Cingolani L, Goda Y. Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci. 2008 May;9(5):344-56. [PubMed].

Long JB, Van Vactor D. Embryonic and larval neural connectivity: progressive changes in synapse form and function at the neuromuscular junction mediated by cytoskeletal regulation. Wiley Interdiscip Rev Dev Biol. 2013 Nov-Dec;2(6):747-65. doi: 10.1002/wdev.114. Epub 2013 Mar 15. [PubMed].

 

Image on home page: Insect neuromuscular junction, M. Sulkowski, NICHD. CC BY 2.0 license.

actin disease-als neuromuscular junction profilin topic-preclinical topic-researchmodels
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