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. Epub 2016 Sep 28 PubMed.
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Washington University
This is very nice work from the same team of labs at UMass that first described and characterized the profilin 1 (PFN1) mutations in familial ALS patients just four years ago. Excitingly, they’ve found that high neuronal expression levels of the ALS-causing C71G mutant PFN1, but not similar expression of wild-type PFN1, result in many of the characteristic phenotypes associated with ALS, including adult-onset muscle weakness progressing to paralysis and lethality in their transgenic mice. The authors thoroughly characterized the mutant mice and they show that the ALS-like symptoms are proceeded by prominent axonal degeneration, denervation at neuromuscular junctions, neuroinflammation, and finally drastic spinal cord motor neuron loss. Importantly, the authors also demonstrate that although their transgene and mutant PFN1 protein are highly expressed in other neuron populations (e.g. cortex, hippocampus), the associated cell toxicity is largely confined to the spinal cord motor neurons, with some less severe loss of sensory neurons as well. This selective aspect of their mouse model is critical to future studies of motor neuron susceptibility due to mutant PFN1 expression in ALS.
Yang et al. demonstrate that ubiquitin and p62 are upregulated in motor neurons in the mutant PFN1 mouse, and they propose that this is due to an abnormal proteostasis response. Further investigation into the mutant PFN1 pathology in these mice is warranted. The authors note that the immunostaining for mutant PFN1 shows “small particulates in the cytoplasm and neuronal processes.” These are remarkably similar in appearance to stress granules. Given that we demonstrated PFN1 can itself be a component of stress granules (Figley et al., 2014), it will be interesting to see if these mutant PFN1 aggregates in vivo also contain stress granule proteins, as are often observed in other ALS-related neuropathology. It will also be of interest to test if the mutant PFN1 aggregates contain other known ALS-associated proteins like TDP-43, FUS, or ataxin 2, especially since several groups have now reported mutant PFN1 interacting with TDP-43 (Wu et al., 2012; Tanaka et al., 2016; Matsukawa et al., 2016).
Hopefully, this PFN1 mouse model will gain traction among ALS researchers similar to the widely used mutant SOD1 mouse, with which it shares several important ALS-like characteristics noted above. Much work remains to be done to determine the mechanism of PFN1 motor neuron toxicity, but this new mouse model will likely be a vital tool in those pursuits.
References:
Figley MD, Bieri G, Kolaitis RM, Taylor JP, Gitler AD. Profilin 1 associates with stress granules and ALS-linked mutations alter stress granule dynamics. J Neurosci. 2014 Jun 11;34(24):8083-97. 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, Landers JE. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012 Aug 23;488(7412):499-503. PubMed.
Tanaka Y, Nonaka T, Suzuki G, Kametani F, Hasegawa M. 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.
Matsukawa K, Hashimoto T, Matsumoto T, Ihara R, Chihara T, Miura M, Wakabayashi T, Iwatsubo T. 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.
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