Developmental expression of mutant PFN1 in motor neurons impacts neuronal growth and motor performance of young and adult mice

Merryn Brettle, Holly Stefen, Aleksandra Djordjevic, Sandra Y. Y. Fok, Josephine W. Chan, Annika van Hummel, Julia van der Hoven, Magdalena Przybyla, Alexander Volkerling, Yazi D. Ke, Fabien Delerue, Lars M. Ittner, Thomas Fath*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment and no cure. Mutations in profilin 1 were identified as a cause of familial ALS (fALS) in 2012. We investigated the functional impact of mutant profilin 1 expression in spinal cords during mouse development. We developed a novel mouse model with the expression of profilin 1 C71G under the control of the Hb9 promoter, targeting expression to α-motor neurons in the spinal cord during development. Embryos of transgenic mice showed evidence of a significant reduction of brachial nerve diameter and a loss of Mendelian inheritance. Despite the lack of transgene expression, adult mice presented with significant motor deficits. Transgenic mice had a significant reduction in the number of motor neurons in the spinal cord. Further analysis of these motor neurons in aged transgenic mice revealed reduced levels of TDP-43 and ChAT expression. Although profilin 1 C71G was only expressed during development, adult mice presented with some ALS-associated pathology and motor symptoms. This study highlights the effect of profilin 1 during neurodevelopment and the impact that this may have in later ALS.

Original languageEnglish
Article number231
Pages (from-to)1-12
Number of pages12
JournalFrontiers in Molecular Neuroscience
Volume12
DOIs
Publication statusPublished - 27 Sep 2019

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • actin
  • amyotrophic lateral sclerosis
  • motor neurons
  • neurodegeneration
  • profilin 1

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