. ALS-causing mutations in profilin-1 alter its conformational dynamics: A computational approach to explain propensity for aggregation. Sci Rep. 2018 Aug 30;8(1):13102. PubMed.


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  1. The mechanism of how PFN1 mutations cause familial ALS is still unclear, but these mutations are autosomal-dominant and mutants are destabilized and prone to form aggregates (Boopathy et al., 2015). Therefore, gain of toxic function of mutant PFN1 would at least partially contribute to the onset or progress of the disease. In fact, we previously showed the toxicity of PFN1 mutants in disorganizing TDP-43, which is the central molecule of ALS (Tanaka et al., 2016; Matsukawa et al., 2016). Interestingly, recent preprint shows that PFN1 mutants (C71G, G118V, E117G) disrupts the liquid-liquid phase separation that organizes membrane-less organelles, while wild-type PFN1 doesn’t change such dynamics (Kang et al., 2018). The mechanism whereby ALS-linked PFN1 induces seed-dependent intracellular TDP-43 aggregation remains unknown, but misfolded PFN1 might be a key to induce conformational changes in TDP-43. This study by Kiaei et al., shows that the change of flexibility of the actin or PLP binding site might increase the propensity for PFN1 to aggregate. In other words, the possible changes on the binding site in PFN1 might cause PFN1 aggregation. Considering that TDP-43 accumulates in sporadic ALS patients, PFN1 abnormality might not be restricted to familial ALS.


    . Structural basis for mutation-induced destabilization of profilin 1 in ALS. Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):7984-9. Epub 2015 Jun 8 PubMed.

    . Gain-of-function profilin 1 mutations linked to familial amyotrophic lateral sclerosis cause seed-dependent intracellular TDP-43 aggregation. Hum Mol Genet. 2016 Apr 1;25(7):1420-33. Epub 2016 Jan 28 PubMed.

    . Familial Amyotrophic Lateral Sclerosis-linked Mutations in Profilin 1 Exacerbate TDP-43-induced Degeneration in the Retina of Drosophila melanogaster through an Increase in the Cytoplasmic Localization of TDP-43. J Biol Chem. 2016 Nov 4;291(45):23464-23476. Epub 2016 Sep 15 PubMed.

    . Misfolded proteins share a common capacity in disrupting LLPS organizing membrane-less organelles. bioRχiv. 2018

    View all comments by Yoshinori Tanaka
  2. In this paper, Kiaei and colleagues have taken a unique approach to investigate how mutations in the profilin gene affect the three-dimensional structure of the protein and its interaction with binding partners. This study, even though mainly performed in silico, offers insight into potential interaction problems that occur due to mutations. Studies like this are important for drug discovery efforts, as they reveal potential sites for drug-target interaction. I wish we had similar studies for all other protein products of genes that are mutated in ALS patients. I congratulate Kiaei and colleagues for this insightful and out-of-the-box research endeavor.

    View all comments by P. Hande Ozdinler
  3. I appreciate the interesting points in two separate comments by Drs. Tanaka and Ozdinler.

    The published work of Tanaka’s group on the role of mutant PFN1 disorganizing TDP-43 is of great interest and is consistent with the evidence that we presented that in our mutant PFN1 mouse model that TDP-43 was abnormally distributed and appeared aggregated spinal cord (Fil et al., 2017). The suggestion by Tanaka that PFN1 abnormality could occur in sporadic ALS is actually very reasonable. This is a highly important hypothesis that can be tested if suitable PFN1 antibodies become available.

    By pointing to the main outcome of this work and how it can be applied toward drug discovery efforts, the comment and feedback by Ozdinler on the nicely written report by Jessica Shugart emphasize the value and impact of a study like this and are highly encouraging. We are currently pushing forward with promising follow-on studies toward developing compounds to reverse the changes that we described in our paper and block the aggregation of mutant PFN1.


    . Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease. Hum Mol Genet. 2017 Feb 15;26(4):686-701. PubMed.

    View all comments by Mahmoud Kiaei

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  1. ALS Mutations Stiffen Profilin, Steer Protein Toward Aggregation