Genetic modifiers ameliorate endocytic and neuromuscular defects in a model of spinal muscular atrophy

Research output: Contribution to journalResearch articleContributedpeer-review


  • Melissa B Walsh - , Brown University (Author)
  • Eva Janzen - , German Sport University Cologne (Author)
  • Emily Wingrove - , Brown University (Author)
  • Seyyedmohsen Hosseinibarkooie - , German Sport University Cologne (Author)
  • Natalia Rodriguez Muela - , Selective neuronal vulnerability in neurodegenerative diseases (Junior Research Group), Harvard University (Author)
  • Lance Davidow - , Harvard University (Author)
  • Maria Dimitriadi - , University of Hertfordshire (Author)
  • Erika M Norabuena - , Harvard University (Author)
  • Lee L Rubin - , Harvard University (Author)
  • Brunhilde Wirth - , German Sport University Cologne (Author)
  • Anne C Hart - , Brown University (Author)


BACKGROUND: Understanding the genetic modifiers of neurodegenerative diseases can provide insight into the mechanisms underlying these disorders. Here, we examine the relationship between the motor neuron disease spinal muscular atrophy (SMA), which is caused by reduced levels of the survival of motor neuron (SMN) protein, and the actin-bundling protein Plastin 3 (PLS3). Increased PLS3 levels suppress symptoms in a subset of SMA patients and ameliorate defects in SMA disease models, but the functional connection between PLS3 and SMN is poorly understood.

RESULTS: We provide immunohistochemical and biochemical evidence for large protein complexes localized in vertebrate motor neuron processes that contain PLS3, SMN, and members of the hnRNP F/H family of proteins. Using a Caenorhabditis elegans (C. elegans) SMA model, we determine that overexpression of PLS3 or loss of the C. elegans hnRNP F/H ortholog SYM-2 enhances endocytic function and ameliorates neuromuscular defects caused by decreased SMN-1 levels. Furthermore, either increasing PLS3 or decreasing SYM-2 levels suppresses defects in a C. elegans ALS model.

CONCLUSIONS: We propose that hnRNP F/H act in the same protein complex as PLS3 and SMN and that the function of this complex is critical for endocytic pathways, suggesting that hnRNP F/H proteins could be potential targets for therapy development.


Original languageEnglish
Article number127
JournalBMC biology
Issue number1
Publication statusPublished - 16 Sep 2020

External IDs

PubMedCentral PMC7495824
Scopus 85091128650



  • Animals, Animals, Genetically Modified/physiology, Caenorhabditis elegans/genetics, Caenorhabditis elegans Proteins/genetics, Disease Models, Animal, Endocytosis/genetics, Membrane Glycoproteins/genetics, Microfilament Proteins/genetics, Muscular Atrophy, Spinal/genetics, RNA-Binding Proteins/genetics, Survival of Motor Neuron 1 Protein/genetics

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