Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease

Daniel Fil, Abigail DeLoach, Shilpi Yadav, Duah Alkam, Melanie MacNicol, Awantika Singh, Cesar M. Compadre, Joseph J. Goellner, Charles A. O'Brien, Tariq Fahmi, Alexei G. Basnakian, Noel Y. Calingasan, Jodi L. Klessner, Flint M. Beal, Owen M. Peters, Jake Metterville, Robert H. Brown, Karen K.Y. Ling, Frank Rigo, P. Hande OzdinlerMahmoud Kiaei*

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

The recent identification of profilin1 mutations in 25 familial ALS cases has linked altered function of this cytoskeletonregulating protein to the pathogenesis of motor neuron disease. To investigate the pathological role of mutant profilin1 in motor neuron disease, we generated transgenic lines of mice expressing human profilin1 with a mutation at position 118 (hPFN1G118V). One of the mouse lines expressing high levels of mutant human PFN1 protein in the brain and spinal cord exhibited many key clinical and pathological features consistent with human ALS disease. These include loss of lower (ventral horn) and upper motor neurons (corticospinal motor neurons in layer V), mutant profilin1 aggregation, abnormally ubiquitinated proteins, reduced choline acetyltransferase (ChAT) enzyme expression, fragmented mitochondria, glial cell activation, muscle atrophy, weight loss, and reduced survival. Our investigations of actin dynamics and axonal integrity suggest that mutant PFN1 protein is associated with an abnormally low filamentous/globular (F/G)-actin ratio that may be the underlying cause of severe damage to ventral root axons resulting in a Wallerian-like degeneration. These observations indicate that our novel profilin1 mutant mouse line may provide a new ALS model with the opportunity to gain unique perspectives into mechanisms of neurodegeneration that contribute to ALS pathogenesis.

Original languageEnglish (US)
Pages (from-to)686-701
Number of pages16
JournalHuman molecular genetics
Volume26
Issue number4
DOIs
StatePublished - Feb 15 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Fil, D., DeLoach, A., Yadav, S., Alkam, D., MacNicol, M., Singh, A., Compadre, C. M., Goellner, J. J., O'Brien, C. A., Fahmi, T., Basnakian, A. G., Calingasan, N. Y., Klessner, J. L., Beal, F. M., Peters, O. M., Metterville, J., Brown, R. H., Ling, K. K. Y., Rigo, F., ... Kiaei, M. (2017). Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease. Human molecular genetics, 26(4), 686-701. https://doi.org/10.1093/hmg/ddw429